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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Synaptic Neurosci.</journal-id>
<journal-title>Frontiers in Synaptic Neuroscience</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Synaptic Neurosci.</abbrev-journal-title>
<issn pub-type="epub">1663-3563</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fnsyn.2020.584536</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Neuroscience</subject>
<subj-group>
<subject>Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>From Synaptic Protein to Prion: The Long and Controversial Journey of &#x003B1;-Synuclein</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes">
<name><surname>Heras-Garvin</surname> <given-names>Antonio</given-names></name>
<xref ref-type="corresp" rid="c001"><sup>&#x0002A;</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/916404/overview"/>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name><surname>Stefanova</surname> <given-names>Nadia</given-names></name>
<xref ref-type="corresp" rid="c001"><sup>&#x0002A;</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/311448/overview"/>
</contrib>
</contrib-group>
<aff><institution>Division of Neurobiology, Department of Neurology, Medical University of Innsbruck</institution>, <addr-line>Innsbruck</addr-line>, <country>Austria</country></aff>
<author-notes>
<fn fn-type="edited-by"><p>Edited by: Taher Darreh-Shori, Karolinska Institutet (KI), Sweden</p></fn>
<fn fn-type="edited-by"><p>Reviewed by: Paolo Calabresi, Catholic University of the Sacred Heart, Italy; Qihui Wu, University of Pennsylvania, United States</p></fn>
<corresp id="c001">&#x0002A;Correspondence: Antonio Heras-Garvin <email>antonio.heras&#x00040;i-med.ac.at</email> Nadia Stefanova <email>nadia.stefanova&#x00040;i-med.ac.at</email></corresp>
</author-notes>
<pub-date pub-type="epub">
<day>21</day>
<month>09</month>
<year>2020</year>
</pub-date>
<pub-date pub-type="collection">
<year>2020</year>
</pub-date>
<volume>12</volume>
<elocation-id>584536</elocation-id>
<history>
<date date-type="received">
<day>17</day>
<month>07</month>
<year>2020</year>
</date>
<date date-type="accepted">
<day>26</day>
<month>08</month>
<year>2020</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#x000A9; 2020 Heras-Garvin and Stefanova.</copyright-statement>
<copyright-year>2020</copyright-year>
<copyright-holder>Heras-Garvin and Stefanova</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract><p>Since its discovery 30 years ago, &#x003B1;-synuclein (&#x003B1;-syn) has been one of the most studied proteins in the field of neuroscience. Dozens of groups worldwide have tried to reveal not only its role in the CNS but also in other organs. &#x003B1;-syn has been linked to several processes essential in brain homeostasis such as neurotransmitter release, synaptic function, and plasticity. However, despite the efforts made in this direction, the main function of &#x003B1;-syn is still unknown. Moreover, &#x003B1;-syn became a protein of interest for neurologists and neuroscientists when mutations in its gene were found associated with Parkinson&#x02019;s disease (PD) and even more when &#x003B1;-syn protein deposits were observed in the brain of PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) patients. At present, the abnormal accumulation of &#x003B1;-syn constitutes one of the pathological hallmarks of these disorders, also referred to as &#x003B1;-synucleinopathies, and it is used for post-mortem diagnostic criteria. Whether &#x003B1;-syn aggregation is cause or consequence of the pathogenic events underlying &#x003B1;-synucleinopathies remains unclear and under discussion. Recently, different <italic>in vitro</italic> and <italic>in vivo</italic> studies have shown the ability of pathogenic &#x003B1;-syn to spread between cells, not only within the CNS but also from peripheral locations such as the gut, salivary glands, and through the olfactory network into the CNS, inducing abnormal misfolding of endogenous &#x003B1;-syn and leading to neurodegeneration and motor and cognitive impairment in animal models. Thus, it has been suggested that &#x003B1;-syn should be considered a prion protein. Here we present an update of what we know about &#x003B1;-syn function, aggregation and spreading, and its role in neurodegeneration. We also discuss the rationale and findings supporting the hypothetical prion nature of &#x003B1;-syn, its weaknesses, and future perspectives for research and the development of disease-modifying therapies.</p></abstract>
<kwd-group>
<kwd>&#x003B1;-synuclein</kwd>
<kwd>&#x003B1;-synucleinopathies</kwd>
<kwd>Parkinson&#x02019;s disease</kwd>
<kwd>neurodegeneration</kwd>
<kwd>prion</kwd>
</kwd-group>
<contract-num rid="cn001">F4414</contract-num>
<contract-sponsor id="cn001">Austrian Science Fund<named-content content-type="fundref-id">10.13039/501100002428</named-content></contract-sponsor>
<counts>
<fig-count count="4"/>
<table-count count="0"/>
<equation-count count="0"/>
<ref-count count="294"/>
<page-count count="18"/>
<word-count count="16675"/>
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</article-meta>
</front>
<body>
<sec sec-type="introduction" id="s1">
<title>Introduction</title>
<p>&#x003B1;-synuclein (&#x003B1;-syn) is one of the most abundant proteins in the nervous system, encoded by the <italic>SNCA</italic> gene. With a molecular mass of approximately 15 kDa, &#x003B1;-syn is composed of 140 amino acid residues (Lee and Trojanowski, <xref ref-type="bibr" rid="B147">2006</xref>; Bendor et al., <xref ref-type="bibr" rid="B20">2013</xref>). &#x003B1;-syn presents three domains: the C-terminal domain, the central domain, or &#x0201C;non-amyloid component&#x0201D; (NAC), which permits its oligomerization due to its hydrophobic composition, and the N-terminal domain, that forms an alpha helix allowing &#x003B1;-syn-lipid interaction (Lashuel et al., <xref ref-type="bibr" rid="B140">2013</xref>). However, despite the efforts made since its discovery, its precise native structure is still unclear and under discussion. It has been proposed that, in physiological conditions, &#x003B1;-syn is mainly found in its monomeric form, either as a soluble intrinsically disordered protein in the cytoplasm of neurons (Binolfi et al., <xref ref-type="bibr" rid="B24">2012</xref>; Fauvet et al., <xref ref-type="bibr" rid="B77">2012</xref>; Theillet et al., <xref ref-type="bibr" rid="B260">2016</xref>), or in an alpha-helical conformation (Bartels et al., <xref ref-type="bibr" rid="B13">2011</xref>; Wang et al., <xref ref-type="bibr" rid="B280">2011</xref>), or a combination of the two (Burr&#x000E9; et al., <xref ref-type="bibr" rid="B38">2013</xref>). Moreover, &#x003B1;-syn can undergo a variety of post-translational modifications (PTM; i.e., phosphorylation, glycation, glycosylation, acetylation) that may affect protein structure and function (Giasson et al., <xref ref-type="bibr" rid="B95">2000</xref>; Theillet et al., <xref ref-type="bibr" rid="B260">2016</xref>; Burr&#x000E9; et al., <xref ref-type="bibr" rid="B36">2018</xref>; Meade et al., <xref ref-type="bibr" rid="B182">2019</xref>).</p>
<p>At the cellular level, &#x003B1;-syn can be found in different cellular organelles, including synaptic terminals and the nucleus of neurons (Maroteaux et al., <xref ref-type="bibr" rid="B171">1988</xref>), mitochondria (Li et al., <xref ref-type="bibr" rid="B154">2007</xref>; Devi et al., <xref ref-type="bibr" rid="B59">2008</xref>; Parihar et al., <xref ref-type="bibr" rid="B197">2008</xref>), endoplasmic reticulum (Hoozemans et al., <xref ref-type="bibr" rid="B114">2007</xref>; Guardia-Laguarta et al., <xref ref-type="bibr" rid="B101">2014</xref>), Golgi apparatus (Gosavi et al., <xref ref-type="bibr" rid="B99">2002</xref>; Mori et al., <xref ref-type="bibr" rid="B187">2002</xref>), and in the endolysosomal system (Lee et al., <xref ref-type="bibr" rid="B145">2004</xref>). In this regard, since its discovery, &#x003B1;-syn has been associated or involved in different cellular processes, such as neurotransmission, calcium homeostasis, vesicle transport, mitochondrial function, and gene regulation (<xref ref-type="fig" rid="F1">Figure 1</xref>). However, the physiological function of &#x003B1;-syn in those subcellular compartments is not fully understood. It has been shown that &#x003B1;-syn is involved in the regulation of the membrane lipid content and curvature, therefore playing a role in vesicle budding and trafficking (Chandra et al., <xref ref-type="bibr" rid="B44">2003</xref>; Varkey et al., <xref ref-type="bibr" rid="B272">2010</xref>). Moreover, &#x003B1;-syn plays a role in SNARE complex assembly at presynaptic terminals (Burr&#x000E9; et al., <xref ref-type="bibr" rid="B37">2010</xref>). Studies based on <italic>in situ</italic> proximity ligation assay (PLA) in neurons have demonstrated proximity between &#x003B1;-syn and SNARE proteins in cell bodies and neurites, including VAMP-2, SNAP-25, and syntaxin-1 (Almandoz-Gil et al., <xref ref-type="bibr" rid="B4">2018</xref>). &#x003B1;-syn is also involved in clathrin-mediated endocytosis (Ben Gedalya et al., <xref ref-type="bibr" rid="B19">2009</xref>) and in dopamine content and metabolism (Sidhu et al., <xref ref-type="bibr" rid="B238">2004</xref>; Yu et al., <xref ref-type="bibr" rid="B289">2005</xref>; Al-Wandi et al., <xref ref-type="bibr" rid="B5">2010</xref>). In association with its nuclear localization, &#x003B1;-syn functions as a regulator of gene expression through its direct interaction with DNA (Pinho et al., <xref ref-type="bibr" rid="B208">2019</xref>), chromatin (Vasquez et al., <xref ref-type="bibr" rid="B273">2017</xref>), and transcription factors involved in development, mitochondrial homeostasis and metabolism of energy (Zheng et al., <xref ref-type="bibr" rid="B294">2010</xref>; Decressac et al., <xref ref-type="bibr" rid="B57">2012</xref>; Eschbach et al., <xref ref-type="bibr" rid="B71">2015</xref>; Davidi et al., <xref ref-type="bibr" rid="B55">2020</xref>), as well as through epigenetic mechanism including DNA methylation or histone acetylation (Surguchev and Surguchov, <xref ref-type="bibr" rid="B254">2017</xref>). Furthermore, &#x003B1;-syn directly controls mitochondrial activity and function by modulating membrane potential, calcium homeostasis, cytochrome release, ATP production, and mitochondrial fusion and fission (Vicario et al., <xref ref-type="bibr" rid="B275">2018</xref>). Interestingly, &#x003B1;-syn is also present in blood cells including red blood cells, peripheral blood mononuclear cells, platelets, and in the plasma. However, the role of &#x003B1;-syn in those cells is unclear (Barbour et al., <xref ref-type="bibr" rid="B12">2008</xref>).</p>
<fig id="F1" position="float">
<label>Figure 1</label>
<caption><p>Physiological roles of &#x003B1;-synuclein (&#x003B1;-syn). Schematic overview including some of the cellular processes linked to &#x003B1;-syn in physiological conditions.</p></caption>
<graphic xlink:href="fnsyn-12-584536-g0001.tif"/>
</fig>
<p>The functions and the structure of &#x003B1;-syn have being intensively investigated during the last decades, leading to a better knowledge of the protein and its association with crucial pathways on different cell types in the central nervous system (CNS), however &#x003B1;-syn research remains a priority not only for neuroscientist, but also for clinicians and pharmaceutical companies. The fact that &#x003B1;-syn aggregation and accumulation constitute the main pathological hallmark of a group of neurodegenerative disorders, referred to as &#x003B1;-synucleinopathies, and that mutations of its gene (<italic>SNCA</italic>) are associated with familiar forms of these disorders, has led &#x003B1;-syn to become one of the &#x0201C;most wanted&#x0201D; proteins in the biomedical field. Pre-clinical studies <italic>in vitro</italic> and <italic>in vivo</italic> have shown than &#x003B1;-syn oligomeric species and aggregates induce the impairment of different processes essential for cellular homeostasis, not only in neurons, but also in other cell types. Moreover, inoculation of &#x003B1;-syn oligomers, fibrils or aggregates in animal models, demonstrated the capability of pathogenic forms of &#x003B1;-syn to spread in a prion-like manner, inducing in some cases changes that replicated human pathology, including the clinical presentation. As a result of those observations, some authors have proposed that &#x003B1;-syn should be considered a prion protein. In this review, we discuss the role of &#x003B1;-syn in neurodegeneration, the different findings supporting the prion nature of &#x003B1;-syn, and its consequences for future therapeutic strategies.</p>
</sec>
<sec id="s2">
<title>&#x003B1;-Syn and Neurodegeneration: &#x003B1;-Synucleionopathies</title>
<p>The abnormal aggregation and accumulation of &#x003B1;-syn constitute the main pathological hallmark of Parkinson&#x02019;s disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB; Spillantini et al., <xref ref-type="bibr" rid="B247">1997</xref>, <xref ref-type="bibr" rid="B246">1998</xref>; Goedert and Spillantini, <xref ref-type="bibr" rid="B97">1998</xref>). These three disorders are also known as &#x003B1;-synucleinopathies. Recently, pure autonomic failure (PAF) and REM sleep behavior disorder (RBD) have been suggested to represent prodromal &#x003B1;-synucleinopathies commonly preceding PD or MSA and showing &#x003B1;-syn aggregation in the peripheral and autonomic nervous system (Arai et al., <xref ref-type="bibr" rid="B7">2000</xref>; Kaufmann et al., <xref ref-type="bibr" rid="B131">2001</xref>, <xref ref-type="bibr" rid="B132">2004</xref>; Iranzo et al., <xref ref-type="bibr" rid="B118">2013</xref>; Barber et al., <xref ref-type="bibr" rid="B11">2017</xref>). Polymeropoulos et al. (<xref ref-type="bibr" rid="B209">1996</xref>, <xref ref-type="bibr" rid="B210">1997</xref>) first described the association between &#x003B1;-syn and PD, when they found that individuals with familiar forms of this disorder presented mutations in the SNCA gene (Polymeropoulos et al., <xref ref-type="bibr" rid="B209">1996</xref>, <xref ref-type="bibr" rid="B210">1997</xref>). Soon afterwards Spillantini et al. (<xref ref-type="bibr" rid="B247">1997</xref>, <xref ref-type="bibr" rid="B246">1998</xref>) showed that the abnormal protein aggregates observed in &#x003B1;-synucleinopathies were strongly immunoreactive for &#x003B1;-syn (Spillantini et al., <xref ref-type="bibr" rid="B247">1997</xref>, <xref ref-type="bibr" rid="B246">1998</xref>; Goedert and Spillantini, <xref ref-type="bibr" rid="B97">1998</xref>). Moreover, some <italic>SNCA</italic> gene allelic variants (i.e., SNCA locus triplication) were sufficient to develop a severe early onset PD and DLB (Singleton et al., <xref ref-type="bibr" rid="B239">2003</xref>; Orme et al., <xref ref-type="bibr" rid="B193">2018</xref>; Zafar et al., <xref ref-type="bibr" rid="B290">2018</xref>). Since then, multiple <italic>in vitro</italic> and <italic>in vivo</italic> studies have tried to decipher the mechanisms underlying &#x003B1;-syn misfolding and aggregation, the following cellular and physiological consequences, and their influence in the human pathology.</p>
<p>&#x003B1;-synucleinopathies present a preference for affecting motor, cognitive and autonomic areas, leading to motor dysfunction, cognitive impairment and/or autonomic failure (Marti et al., <xref ref-type="bibr" rid="B173">2003</xref>). Phenotypic diversity, symptom severity and disease duration varies among these disorders based on the affectation of different neuroanatomical regions, selective vulnerability of different cell types and the extent of the pathology (Marti et al., <xref ref-type="bibr" rid="B173">2003</xref>). Pathologically, PD and DLB are characterized by the abnormal accumulation of &#x003B1;-syn in the cytoplasm of neurons, in the so-called Lewy bodies (LBs; Spillantini et al., <xref ref-type="bibr" rid="B246">1998</xref>). Associated with the presence of LBs in cortical and subcortical areas, post-mortem evaluation of PD and DLB brains show a preferential loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), neuronal loss in the locus coeruleus (LC) and cortical atrophy (Dickson et al., <xref ref-type="bibr" rid="B62">2009</xref>; Cheng et al., <xref ref-type="bibr" rid="B47">2010</xref>; Jellinger, <xref ref-type="bibr" rid="B123">2018</xref>). In addition to that, other neuronal populations in the brainstem accumulate LBs and degenerate, probably leading to many of the secondary clinical features of PD and DLB, such as autonomic dysfunction or sleep disturbances (Coon et al., <xref ref-type="bibr" rid="B51">2018</xref>; Outeiro et al., <xref ref-type="bibr" rid="B194">2019</xref>). In PAF, typical LBs are present in sympathetic ganglia, distal sympathetic nerves, substantia nigra, and locus ceruleus. In correlation with the presence of LBs, PAF patients present a significant unmyelinated nerve fiber density compared to healthy controls and neuronal degeneration in preganglionic sympathetic intermediolateral column and paravertebral ganglia (Kaufmann et al., <xref ref-type="bibr" rid="B131">2001</xref>; Thaisetthawatkul, <xref ref-type="bibr" rid="B259">2016</xref>). In MSA, however, &#x003B1;-syn mainly (but not exclusively) accumulates throughout the neocortex, hippocampus, brainstem, spinal cord, and dorsal root ganglia in the cytoplasm of oligodendrocytes, in the so-called glial cytoplasmic inclusions (GCIs), associating with striatonigral degeneration (SND), olivopontocerebellar atrophy and cell loss in LC and brainstem nuclei, leading to parkinsonism, cerebellar symptoms and autonomic dysfunction (Fanciulli and Wenning, <xref ref-type="bibr" rid="B75">2015</xref>).</p>
<p>Despite the different clinical features of &#x003B1;-synucleinopathies, these disorders share characteristics such as neurodegeneration, neuroinflammation and demyelination, among others. Based on <italic>in vitro</italic> and <italic>in vivo</italic> studies, &#x003B1;-syn seems to play a central role in the pathological changes through a direct interaction with components of cellular pathways essential for cell homeostasis (<xref ref-type="fig" rid="F2">Figure 2</xref>). Thus, pathological &#x003B1;-syn is able to bind and inhibit lysosomal function (Mazzulli et al., <xref ref-type="bibr" rid="B179">2016</xref>; Flavin et al., <xref ref-type="bibr" rid="B82">2017</xref>), proteasomal activity (Stefanis et al., <xref ref-type="bibr" rid="B248">2001</xref>; Tanaka et al., <xref ref-type="bibr" rid="B257">2001</xref>; Petrucelli et al., <xref ref-type="bibr" rid="B206">2002</xref>; Snyder et al., <xref ref-type="bibr" rid="B241">2003</xref>; Lindersson et al., <xref ref-type="bibr" rid="B155">2004</xref>; Emmanouilidou et al., <xref ref-type="bibr" rid="B69">2010</xref>), to impair axonal transport (Volpicelli-Daley, <xref ref-type="bibr" rid="B277">2017</xref>), and to induce Ca<sup>2+</sup> dyshomeostasis (Danzer et al., <xref ref-type="bibr" rid="B54">2007</xref>; Chen Y. et al., <xref ref-type="bibr" rid="B46">2015</xref>; Angelova et al., <xref ref-type="bibr" rid="B6">2016</xref>) and mitochondrial dysfunction (Di Maio et al., <xref ref-type="bibr" rid="B61">2016</xref>; Ganjam et al., <xref ref-type="bibr" rid="B88">2019</xref>; Wang et al., <xref ref-type="bibr" rid="B281">2019</xref>; Park et al., <xref ref-type="bibr" rid="B199">2020</xref>). Latter promotes the generation of reactive oxygen species (ROS), and therefore oxidative stress, which may lead to mitochondrial damage, the release of cytochrome c to the cytoplasm, and cell death (Hsu et al., <xref ref-type="bibr" rid="B115">2000</xref>; Smith et al., <xref ref-type="bibr" rid="B240">2005</xref>; Parihar et al., <xref ref-type="bibr" rid="B197">2008</xref>; Reeve et al., <xref ref-type="bibr" rid="B220">2015</xref>; Tapias et al., <xref ref-type="bibr" rid="B258">2017</xref>; Ludtmann et al., <xref ref-type="bibr" rid="B160">2018</xref>). Associated with its nuclear localization or its capacity to promote oxidative stress, recent studies suggested an involvement of &#x003B1;-syn in DNA damage (Paiva et al., <xref ref-type="bibr" rid="B196">2017</xref>; Vasquez et al., <xref ref-type="bibr" rid="B273">2017</xref>; Milanese et al., <xref ref-type="bibr" rid="B185">2018</xref>; Schaser et al., <xref ref-type="bibr" rid="B229">2019</xref>). Pathological &#x003B1;-syn also promotes pathogenic redistribution of membrane proteins (Shrivastava et al., <xref ref-type="bibr" rid="B236">2015</xref>, <xref ref-type="bibr" rid="B235">2020</xref>) and interferes with the normal function of cell membranes, facilitating diffusion of molecules and ions, specially Ca<sup>2+</sup>, and inducing cell damage (Tosatto et al., <xref ref-type="bibr" rid="B263">2012</xref>; Tsigelny et al., <xref ref-type="bibr" rid="B266">2012</xref>; Angelova et al., <xref ref-type="bibr" rid="B6">2016</xref>; Fusco et al., <xref ref-type="bibr" rid="B86">2017</xref>; Dong et al., <xref ref-type="bibr" rid="B65">2018</xref>). The impairment of all these cellular processes may be especially significant in dopaminergic neurons, since dopamine promotes the formation of pathological &#x003B1;-syn species (Cappai et al., <xref ref-type="bibr" rid="B42">2005</xref>; Lee et al., <xref ref-type="bibr" rid="B144">2011</xref>; Mor et al., <xref ref-type="bibr" rid="B186">2017</xref>). Thus, a multi-hit model has been proposed, in which the synergistic interaction between &#x003B1;-syn, dopamine and Ca<sup>2+</sup> in neurons may underlie neuronal loss in SNpc and LC (Post et al., <xref ref-type="bibr" rid="B211">2018</xref>). Neurodegeneration in the LC may induce a direct loss of norepinephrine (NE), however, &#x003B1;-syn is also able to translocate to the nucleus of NE-producing cells and interfere with transcription of dopamine &#x000DF;-hydroxylase, the final enzyme in NE biosynthesis, disrupting NE production and leading to a reduction of neurotrophic factor signaling, indirectly altering innate and adaptive immune response and worsening central and peripheral inflammation (Butkovich et al., <xref ref-type="bibr" rid="B39">2018</xref>).</p>
<fig id="F2" position="float">
<label>Figure 2</label>
<caption><p>Pathological roles of &#x003B1;-syn. Schematic overview including some of the cellular processes (left) and histopathological events (right) associated with the presence of pathogenic &#x003B1;-syn species.</p></caption>
<graphic xlink:href="fnsyn-12-584536-g0002.tif"/>
</fig>
<p>Different <italic>in vivo</italic> and <italic>in vitro</italic> studies have also shown the ability of pathological &#x003B1;-syn to induce synaptic dysfunction, both at the presynaptic and postsynaptic terminal (Ghiglieri et al., <xref ref-type="bibr" rid="B93">2018</xref>). At presynaptic level, pathological &#x003B1;-syn seems to affect synaptic vesicle pool, trafficking and endocytosis by interfering with the exo-endocytotic cycling machinery, thus suggesting the possible association between &#x003B1;-syn pathology and impaired synaptic function even in the absence of cell death (Bridi and Hirth, <xref ref-type="bibr" rid="B32">2018</xref>; Froula et al., <xref ref-type="bibr" rid="B85">2018</xref>; Wu et al., <xref ref-type="bibr" rid="B287">2019</xref>). At a postsynaptic level, <italic>in vivo</italic> studies have shown that pathological &#x003B1;-syn reduces striatal dopamine, NMDA receptor-mediated synaptic currents, impairs early memory and motor learning, and prevents long-term potentiation of cholinergic interneurons and spiny projection neurons in the striatum even at early stages of the disease (Tozzi et al., <xref ref-type="bibr" rid="B264">2016</xref>; Phan et al., <xref ref-type="bibr" rid="B207">2017</xref>; Giordano et al., <xref ref-type="bibr" rid="B96">2018</xref>; Durante et al., <xref ref-type="bibr" rid="B67">2019</xref>).</p>
<p>Pathological &#x003B1;-syn can also modulate neuroinflammation (<xref ref-type="fig" rid="F2">Figure 2</xref>) directly through different mechanism including the activation of microglial cells (Austin et al., <xref ref-type="bibr" rid="B10">2006</xref>; Su et al., <xref ref-type="bibr" rid="B251">2008</xref>; Theodore et al., <xref ref-type="bibr" rid="B261">2008</xref>; Fellner et al., <xref ref-type="bibr" rid="B79">2013</xref>; Choi et al., <xref ref-type="bibr" rid="B48">2020</xref>), which induces a robust pro-inflammatory response (Kim et al., <xref ref-type="bibr" rid="B133">2013</xref>; Sarkar et al., <xref ref-type="bibr" rid="B227">2020</xref>) leading to increased &#x003B1;-syn aggregation and potentiating neurodegeneration (Zhang et al., <xref ref-type="bibr" rid="B292">2005</xref>; Stefanova et al., <xref ref-type="bibr" rid="B249">2007</xref>). In this regard, microgliosis has been shown in post-mortem studies and in PET imaging analysis of patients diagnosed with &#x003B1;-synucleinopathies (McGeer et al., <xref ref-type="bibr" rid="B181">1988a</xref>; Gerhard et al., <xref ref-type="bibr" rid="B91">2003</xref>, <xref ref-type="bibr" rid="B92">2006</xref>; Doorn et al., <xref ref-type="bibr" rid="B66">2014</xref>; Stokholm et al., <xref ref-type="bibr" rid="B250">2017</xref>; Surendranathan et al., <xref ref-type="bibr" rid="B253">2018</xref>). In addition, microgliosis paralleled system degeneration in patients and was associated with &#x003B1;-syn inclusions (Imamura et al., <xref ref-type="bibr" rid="B117">2003</xref>; Ishizawa et al., <xref ref-type="bibr" rid="B121">2004</xref>, <xref ref-type="bibr" rid="B120">2008</xref>; Croisier et al., <xref ref-type="bibr" rid="B53">2005</xref>; Kubler et al., <xref ref-type="bibr" rid="B139">2019</xref>). A recent study with PD patients engrafted with foetal embryonic dopaminergic neurons showed microglia activation in all grafts before &#x003B1;-syn aggregates were detected (Olanow et al., <xref ref-type="bibr" rid="B190">2019</xref>). The authors speculated that microglial activation could have been initiated by the presence of endogenous pathological &#x003B1;-syn in patients, by an immune reaction due to the implantation of foreign tissue or by the surgical procedure itself (Olanow et al., <xref ref-type="bibr" rid="B190">2019</xref>). Moreover, we recently showed that targeting &#x003B1;-syn oligomerization in an animal model for MSA led to a decrease of &#x003B1;-syn aggregates which significantly correlated with neuroprotection and a reduction in microglial activation (Heras-Garvin et al., <xref ref-type="bibr" rid="B109">2019</xref>).</p>
<p>Similar to microglial cells, pathological &#x003B1;-syn also induces activation of astrocytes (<xref ref-type="fig" rid="F2">Figure 2</xref>), aggravating neuroinflammation (Lee et al., <xref ref-type="bibr" rid="B146">2010</xref>; Fellner et al., <xref ref-type="bibr" rid="B79">2013</xref>; Radford et al., <xref ref-type="bibr" rid="B216">2015</xref>). Astrogliosis has also been described in &#x003B1;-synucleinopathies paralleling the neurodegenerative process (Ozawa et al., <xref ref-type="bibr" rid="B195">2004</xref>; Miklossy et al., <xref ref-type="bibr" rid="B184">2006</xref>; Radford et al., <xref ref-type="bibr" rid="B216">2015</xref>). Moreover, &#x003B1;-syn inclusions are often found in the cytoplasm of astrocytes and may lead to astrocyte dysfunction (Song et al., <xref ref-type="bibr" rid="B243">2009</xref>; Halliday and Stevens, <xref ref-type="bibr" rid="B106">2011</xref>; Sorrentino et al., <xref ref-type="bibr" rid="B245">2019</xref>). Even a role of the adaptive immune system in PD has been proposed. Post-mortem evaluation showed higher numbers of T cells in the ventral midbrain of PD brains and mouse models than in healthy controls, suggesting a targeted extravasation, and supporting a role for T cells in disease pathogenesis (McGeer et al., <xref ref-type="bibr" rid="B180">1988b</xref>; Theodore et al., <xref ref-type="bibr" rid="B261">2008</xref>; Brochard et al., <xref ref-type="bibr" rid="B33">2009</xref>; Sommer et al., <xref ref-type="bibr" rid="B242">2018</xref>). Recent studies showed the presence of &#x003B1;-syn-specific T cells in PD patients, and therefore an autoimmune response to &#x003B1;-syn (Sulzer et al., <xref ref-type="bibr" rid="B252">2017</xref>; Garretti et al., <xref ref-type="bibr" rid="B90">2019</xref>). However, at present, &#x003B1;-syn-specific T cells have only been detected in the periphery of PD patients. Whether these cells are able to infiltrate into the CNS and cause dopaminergic neuron death remains to be determined.</p>
<p>Although most research on the pathogenic role of &#x003B1;-syn have been focused in neurons, microglia and astrocytes, there have also been studies that evaluated the deleterious effect of pathogenic &#x003B1;-syn in oligodendrocytes and oligodendroglial precursor cells (OPCs), which are essential to understand the cellular and molecular consequences of &#x003B1;-syn accumulation in MSA (<xref ref-type="fig" rid="F2">Figure 2</xref>). Over-expression of &#x003B1;-syn or the addition of exogenous pathological &#x003B1;-syn severely impaired myelin formation <italic>in vitro</italic> and <italic>in vivo</italic> (Ettle et al., <xref ref-type="bibr" rid="B73">2016</xref>; Mandel et al., <xref ref-type="bibr" rid="B166">2017</xref>; Mavroeidi et al., <xref ref-type="bibr" rid="B177">2019</xref>), corroborating the demyelination observed in MSA brains (Song et al., <xref ref-type="bibr" rid="B244">2007</xref>; Don et al., <xref ref-type="bibr" rid="B64">2014</xref>; Ettle et al., <xref ref-type="bibr" rid="B73">2016</xref>). This effect seems to be mediated by the interference of &#x003B1;-syn with the expression of proteins associated with cholesterol and membrane biogenesis (Ettle et al., <xref ref-type="bibr" rid="B73">2016</xref>; Kaji et al., <xref ref-type="bibr" rid="B125">2018</xref>), and by the partial sequestration of the myelin basic protein (MBP) into GCIs in a process orchestrated by endogenous &#x003B1;-syn and the the oligodendroglial-specific phosphoprotein p25&#x003B1; (Mavroeidi et al., <xref ref-type="bibr" rid="B177">2019</xref>). Moreover, &#x003B1;-syn impairs OPC maturation <italic>in vitro</italic> (Ettle et al., <xref ref-type="bibr" rid="B74">2014</xref>) and in animal models of MSA, where an age-dependent increase of dividing OPCs within the striatum was observed (May et al., <xref ref-type="bibr" rid="B178">2014</xref>). Latter was confirmed after postmortem analysis in MSA patients, revealing &#x003B1;-syn within OPCs and an increased number of striatal OPCs compared to healthy controls (May et al., <xref ref-type="bibr" rid="B178">2014</xref>). &#x003B1;-syn also induces a distinct gene expression profile in oligodendrocytes, including upregulation of cytokines important for myeloid cell attraction and proliferation (Schafferer et al., <xref ref-type="bibr" rid="B228">2016</xref>; Hoffmann et al., <xref ref-type="bibr" rid="B111">2019</xref>), which constitutes an early crosstalk between neuroinflammation and &#x003B1;-syn-mediated oligodendrocyte dysfunction.</p>
<p>Overall, multiple cell populations and pathways can be affected by the abnormal misfolding, aggregation and accumulation of &#x003B1;-syn. Determining which events are primary or secondary in the pathogenesis of &#x003B1;-synucleinopathies will be essential in order to define potential strategies to prevent cell damage and, finally, neurodegeneration.</p>
</sec>
<sec id="s3">
<title>Aggregation and Spreading of &#x003B1;-Syn</title>
<p>As stated before, the normal conformation of &#x003B1;-syn is either a disordered monomer, alpha-helical, or a combination of the two. But, under pathological conditions, monomers can convert to &#x003B2;-sheets by recruiting additional monomers, aggregating and giving rise to oligomers that, eventually, form protofilaments and amyloid fibrils (<xref ref-type="fig" rid="F3">Figure 3</xref>), which can adopt different morphologies such as spherical, chain-like, annular (pore-like structure), and tubular (Cremades and Dobson, <xref ref-type="bibr" rid="B52">2018</xref>). To define the process through which &#x003B1;-syn oligomers give rise to pathological inclusions is challenging due to their transient nature and their ability to rapidly recruit monomeric &#x003B1;-syn to form fibrils. Nevertheless, the recent description that &#x003B1;-syn oligomers can be kinetically trapped made possible to compare the contribution of oligomers and fibrils to different &#x003B1;-synucleinopathy phenotypes (Chen S. W. et al., <xref ref-type="bibr" rid="B45">2015</xref>; Iljina et al., <xref ref-type="bibr" rid="B116">2016</xref>; De Oliveira and Silva, <xref ref-type="bibr" rid="B56">2019</xref>; Froula et al., <xref ref-type="bibr" rid="B84">2019</xref>). It is believed that the formation of &#x003B1;-syn fibrils results from interactions between monomers and oligomers that are thermodynamically favorable and stabilizing (Alam et al., <xref ref-type="bibr" rid="B2">2019</xref>). Despite several studies have associated the presence of &#x003B1;-syn oligomers and fibrillar species with cytotoxicity and neurodegeneration, thus supporting the idea that these &#x003B1;-syn forms are the responsible for the neurodegenerative process observed in &#x003B1;-synucleinoptahies (Alam et al., <xref ref-type="bibr" rid="B2">2019</xref>), a recent publication by Mahul-Mellier et al. (<xref ref-type="bibr" rid="B164">2020</xref>) proposed that the process of LB formation, rather than simply fibril formation, is one of the major drivers of neurodegeneration through disruption of cellular functions, inducing mitochondria damage and deficits, and synaptic dysfunction. Therefore, which &#x003B1;-syn species or processes associated with &#x003B1;-syn aggregation and accumulation are the most toxic is still a matter of debate.</p>
<fig id="F3" position="float">
<label>Figure 3</label>
<caption><p>&#x003B1;-synuclein aggregation process. Schematic overview of the hypothetical aggregation process of monomeric &#x003B1;-syn and the different events that can induce its misfolding and promote aggregation.</p></caption>
<graphic xlink:href="fnsyn-12-584536-g0003.tif"/>
</fig>
<p>Mutations in the <italic>SNCA</italic> gene associated with familiar forms of &#x003B1;-synucleinopathies, such as A30P or A53T, are more prone to aggregate and form fibrillar &#x003B1;-syn oligomers (Lashuel et al., <xref ref-type="bibr" rid="B141">2002</xref>; Bengoa-Vergniory et al., <xref ref-type="bibr" rid="B21">2017</xref>). Different events promote &#x003B1;-syn aggregation (<xref ref-type="fig" rid="F3">Figure 3</xref>), including low pH (Buell et al., <xref ref-type="bibr" rid="B35">2014</xref>). Indeed, neutral pH inhibits the growth of &#x003B1;-syn fibrils, while acidic pH increases it (Grey et al., <xref ref-type="bibr" rid="B100">2011</xref>). Other micro-environmental factors affecting &#x003B1;-syn aggregation include metal ions (Uversky et al., <xref ref-type="bibr" rid="B270">2001</xref>), polyamines (Krasnoslobodtsev et al., <xref ref-type="bibr" rid="B138">2012</xref>; Holmes et al., <xref ref-type="bibr" rid="B112">2013</xref>), proteoglycans (Lashuel et al., <xref ref-type="bibr" rid="B140">2013</xref>), nucleic acids (Hegde and Rao, <xref ref-type="bibr" rid="B107">2007</xref>), poly-ADP ribose (Kam et al., <xref ref-type="bibr" rid="B128">2018</xref>) and fatty acids (Fecchio et al., <xref ref-type="bibr" rid="B78">2018</xref>). &#x003B1;-syn PTM play also a role in its aggregation process. Thus, glycation of &#x003B1;-syn potentiate toxicity and aggregation (Vicente Miranda et al., <xref ref-type="bibr" rid="B276">2017</xref>). Phosphorylation at various sites contributes to &#x003B1;-syn aggregation (Zhang et al., <xref ref-type="bibr" rid="B291">2019</xref>). In particular, phosphorylation at residue Ser129 constitutes one of the most studied &#x003B1;-syn PTM, however, there is contradictory data about its role in pathology, as it was shown to be both protective and toxic (Arawaka et al., <xref ref-type="bibr" rid="B8">2017</xref>; Zhang et al., <xref ref-type="bibr" rid="B291">2019</xref>). In physiological conditions, &#x003B1;-syn is constitutively acetylated in its N-terminal, which seems to make &#x003B1;-syn more resistant to oligomerization and aggregation (Gonzalez et al., <xref ref-type="bibr" rid="B98">2019</xref>). C-terminal truncation of &#x003B1;-syn has been associated with an increase in self-assembly properties and constitutes 10&#x02013;25% of the LBs (Li et al., <xref ref-type="bibr" rid="B153">2005</xref>; Wang et al., <xref ref-type="bibr" rid="B279">2016</xref>). As a result of oxidative stress, the generation of nitric oxide induces nitration of tyrosine residues of &#x003B1;-syn, promoting aggregation (Giasson et al., <xref ref-type="bibr" rid="B95">2000</xref>). SUMOylation inhibits ubiquitin-mediated degradation of &#x003B1;-syn, which leads to an increase of &#x003B1;-syn concentration and aggregation (Rott et al., <xref ref-type="bibr" rid="B224">2017</xref>). Lastly, the aggregation process of &#x003B1;-syn seems to be affected by the presence of other proteins. Although homotypic seeding is the preferred form of aggregation, &#x003B1;-syn can bind other natively unfolded proteins such as tau, PrP<sup>C</sup> or A&#x003B2;, in a process termed heterotypic cross-seeding, which accelerate aggregation and neuropathology (Clinton et al., <xref ref-type="bibr" rid="B50">2010</xref>; Ono et al., <xref ref-type="bibr" rid="B191">2012</xref>; Guo et al., <xref ref-type="bibr" rid="B103">2013</xref>; Katorcha et al., <xref ref-type="bibr" rid="B130">2017</xref>; Bassil et al., <xref ref-type="bibr" rid="B14">2020</xref>). However, despite our knowledge about the different processes that may be involved in its abnormal aggregation, the initial event that triggers &#x003B1;-syn oligomer formation and accumulation remains unknown.</p>
<p>In 2003, after post-mortem evaluation of PD brains, Braak et al. (<xref ref-type="bibr" rid="B27">2003a</xref>) staged the pathology of this disorder. In that study, they defined the earliest phases of the disease, characterized by the presence of &#x003B1;-syn pathology in the anterior olfactory nucleus and in the dorsal motor nucleus of the vagal in the absence of motor symptoms. Based on those findings, Braak et al. (<xref ref-type="bibr" rid="B29">2003b</xref>) developed a theory in which PD might be initiated when a neurotropic agent enters the body by nasal route, through the olfactory epithelium to the olfactory bulb, or by gastric route, infiltrating the gut to the submucous plexus and traveling along preganglionic parasympathetic fibers to the dorsal motor nucleus of the vagus nerve. The presence of LBs in the enteric and peripheral nervous systems supported their claim (Braak et al., <xref ref-type="bibr" rid="B26">2006</xref>, <xref ref-type="bibr" rid="B30">2007</xref>; Shannon et al., <xref ref-type="bibr" rid="B234">2012</xref>). The LB pathology would then travel through the CNS. The authors proposed that PD could be divided into six different stages, each one defined by abnormal pathology in particular neurological structures and specific symptom severity. Thus, early stages would be characterized by non-motor symptoms, including hyposmia and autonomic dysfunction, mid-stages would be characterized by the presence of motor symptoms and later stages by the presence of cognitive impairment (Braak et al., <xref ref-type="bibr" rid="B28">2004</xref>). In their theory, the authors proposed as the possible neurotropic agent a virus or a pathogen composed of fragments of misfolded &#x003B1;-syn that could possess unconventional prion-like properties (Braak et al., <xref ref-type="bibr" rid="B29">2003b</xref>). Over the last decade, different studies have shown that &#x003B1;-syn is in fact not only able to aggregate, but also to spread and propagate the synucleinopathy in a prion-like fashion. This new hypothesis and line of research was initially inspired by the observation that grafts of embryonic dopamine neurons into the brains of human PD patients developed &#x003B1;-syn pathology (Kordower et al., <xref ref-type="bibr" rid="B137">2008</xref>; Li et al., <xref ref-type="bibr" rid="B151">2008</xref>). The authors hypothesized that pathological &#x003B1;-syn from the host was transferred into the young grafted neurons in a prion-like manner (Brundin et al., <xref ref-type="bibr" rid="B34">2008</xref>). Since then, different groups have proven that &#x003B1;-syn is able to be taken up by cells, including dopaminergic neurons (Luk et al., <xref ref-type="bibr" rid="B163">2009</xref>; Volpicelli-Daley et al., <xref ref-type="bibr" rid="B278">2011</xref>), be transmitted from neuron to neuron (Desplats et al., <xref ref-type="bibr" rid="B58">2009</xref>; Freundt et al., <xref ref-type="bibr" rid="B83">2012</xref>), from neurons to oligodendrocytes (Reyes et al., <xref ref-type="bibr" rid="B223">2014</xref>), and to induce the formation of aggregates that share some of the LB features, i.e., a high degree of phosphorylation and polyubiquitination (Volpicelli-Daley et al., <xref ref-type="bibr" rid="B278">2011</xref>). An early work demonstrated the presence of &#x003B1;-syn in plasma and cerebrospinal fluid of PD patients, thus supporting the hypothesis that &#x003B1;-syn may enter cells from the extracellular space (El-Agnaf et al., <xref ref-type="bibr" rid="B68">2003</xref>). Moreover, the inoculation of recombinant &#x003B1;-syn preformed-fibrils (PFFs) or patient-derived pathological &#x003B1;-syn in wildtype and transgenic animals resulted in the development of widespread synucleinopathy throughout synaptically connected networks, neurodegeneration and behavioral deficits, following in some cases a similar pattern to the one define in Braak&#x02019;s hypothesis (Luk et al., <xref ref-type="bibr" rid="B161">2012a</xref>,<xref ref-type="bibr" rid="B162">b</xref>; Masuda-Suzukake et al., <xref ref-type="bibr" rid="B176">2013</xref>; Ulusoy et al., <xref ref-type="bibr" rid="B269">2013</xref>; Holmqvist et al., <xref ref-type="bibr" rid="B113">2014</xref>; Recasens et al., <xref ref-type="bibr" rid="B219">2014</xref>; Paumier et al., <xref ref-type="bibr" rid="B200">2015</xref>; Abdelmotilib et al., <xref ref-type="bibr" rid="B1">2017</xref>; Manfredsson et al., <xref ref-type="bibr" rid="B169">2018</xref>; Rey et al., <xref ref-type="bibr" rid="B222">2018</xref>; Chu et al., <xref ref-type="bibr" rid="B49">2019</xref>; Kim S. et al., <xref ref-type="bibr" rid="B135">2019</xref>; Challis et al., <xref ref-type="bibr" rid="B43">2020</xref>). Additional studies demonstrated that the spreading of &#x003B1;-syn pathology depended on the misfolding and recruitment of endogenous &#x003B1;-syn (Volpicelli-Daley et al., <xref ref-type="bibr" rid="B278">2011</xref>; Kaji et al., <xref ref-type="bibr" rid="B125">2018</xref>; Kim S. et al., <xref ref-type="bibr" rid="B135">2019</xref>; Wu et al., <xref ref-type="bibr" rid="B287">2019</xref>). Furthermore, a recent publication suggested that the inoculation site may determine the synucleinopathy, since autonomic ganglionic injection of &#x003B1;-syn fibrils resulted in a model of PAF (Wang et al., <xref ref-type="bibr" rid="B282">2020</xref>). However, the mechanism involved in &#x003B1;-syn internalization remains unclear. In the last years, several membrane protein receptors have been proposed to play an important role in &#x003B1;-syn uptake, including lymphocyte-activation gene 3 (Mao et al., <xref ref-type="bibr" rid="B170">2016</xref>), Rab proteins (Masaracchia et al., <xref ref-type="bibr" rid="B174">2018</xref>) and flotillin-1 and dopamine transporter (DAT; Kobayashi et al., <xref ref-type="bibr" rid="B136">2019</xref>).</p>
<p>In addition, recent publications have demonstrated the existence of different strains of pathological &#x003B1;-syn which cause distinct synucleinopathies, targeting distinct brain regions and cell types (Bousset et al., <xref ref-type="bibr" rid="B25">2013</xref>; Peelaerts et al., <xref ref-type="bibr" rid="B201">2015</xref>; Rey et al., <xref ref-type="bibr" rid="B221">2019</xref>; Lau et al., <xref ref-type="bibr" rid="B142">2020</xref>). In particular, MSA and PD strains seem to have different structural and seed properties that may be used as differential diagnostic criteria and that could explain the more aggressive and rapid progression of MSA compared to other synucleinopathies (Peng et al., <xref ref-type="bibr" rid="B202">2018b</xref>; Candelise et al., <xref ref-type="bibr" rid="B40">2019</xref>; Yamasaki et al., <xref ref-type="bibr" rid="B288">2019</xref>; Schweighauser et al., <xref ref-type="bibr" rid="B231">2020</xref>; Shahnawaz et al., <xref ref-type="bibr" rid="B233">2020</xref>; Van Der Perren et al., <xref ref-type="bibr" rid="B271">2020</xref>). It is not yet clear how the different &#x003B1;-syn strains are generated, but the cellular micro-environment may play an important role (Candelise et al., <xref ref-type="bibr" rid="B41">2020</xref>). Thus, a recent publication by the group of Virginia Lee showed that the &#x003B1;-syn extracted from GCIs presents a different proteolytic profile and more potent biological activity than the &#x003B1;-syn from LBs and that the specific cellular milieu of oligodendrocytes is responsible for the transformation of misfolded &#x003B1;-syn into the MSA strain (Peng et al., <xref ref-type="bibr" rid="B203">2018a</xref>).</p>
<p>The identification of the mechanisms associated or responsible for &#x003B1;-syn uptake, processing, aggregation and release, and the contribution of different &#x003B1;-syn strains to inclusion formation and to the impairment of cellular pathways will be essential to completely understand the pathogenic process underlying &#x003B1;-synucleinopathies, to identify novel targets for disease modification, the development of new therapeutic strategies and to generate possible biomarkers which would allow the early diagnosis of these disorders.</p>
</sec>
<sec id="s4">
<title>&#x003B1;-Syn, a Prion Protein?</title>
<p>The term prion was first described by Stanley Prusiner as a &#x0201C;small proteinaceous infectious particle which is resistant to inactivation by most procedures that modify nucleic acids&#x0201D; and resulted from the blend of &#x0201C;protein&#x0201D; and &#x0201C;infection&#x0201D; (Prusiner, <xref ref-type="bibr" rid="B214">1982</xref>). Therefore, prions should constitute the underlying cause of an infectious disease that can be transmitted among individuals from the same or different species, and not a secondary consequence of the disease (Prusiner, <xref ref-type="bibr" rid="B215">1998</xref>). In this regard, based on <italic>in vivo</italic> and <italic>in vitro</italic> studies, &#x003B1;-syn seems to exhibit some of the properties of prion proteins (<xref ref-type="fig" rid="F4">Figure 4</xref>), such as the ability to undergo misfolding and to self-propagate, inducing aggregation of endogenous &#x003B1;-syn (Hijaz and Volpicelli-Daley, <xref ref-type="bibr" rid="B110">2020</xref>), to exist as distinct strains (Bousset et al., <xref ref-type="bibr" rid="B25">2013</xref>; Peelaerts et al., <xref ref-type="bibr" rid="B201">2015</xref>; Candelise et al., <xref ref-type="bibr" rid="B40">2019</xref>; Yamasaki et al., <xref ref-type="bibr" rid="B288">2019</xref>; Lau et al., <xref ref-type="bibr" rid="B142">2020</xref>; Schweighauser et al., <xref ref-type="bibr" rid="B231">2020</xref>; Shahnawaz et al., <xref ref-type="bibr" rid="B233">2020</xref>) and to be resistant to inactivation by formaldehyde (Schweighauser et al., <xref ref-type="bibr" rid="B230">2015</xref>; Woerman et al., <xref ref-type="bibr" rid="B286">2018</xref>). As discussed before, the fact that &#x003B1;-syn aggregates were found in human brain regions affected by the disease and that some studies, like the one conducted by Braak et al. (<xref ref-type="bibr" rid="B28">2004</xref>) showed the presence of inclusions in peripheral organs and described an association between disease stage and Lewy pathology, led the authors to propose that &#x003B1;-synucleinopathies could initiate in the gut or the olfactory bulb and slowly spread to the CNS (Beach et al., <xref ref-type="bibr" rid="B15">2009</xref>). This evidence and the data demonstrating the ability of &#x003B1;-syn to propagate from the gut and other peripheral organs in animal models (Kim S. et al., <xref ref-type="bibr" rid="B135">2019</xref>; Lohmann et al., <xref ref-type="bibr" rid="B158">2019</xref>) as well as the finding of LBs in grafted dopaminergic neurons in PD patients (Kordower et al., <xref ref-type="bibr" rid="B137">2008</xref>; Li et al., <xref ref-type="bibr" rid="B151">2008</xref>) supported the prion nature of &#x003B1;-syn.</p>
<fig id="F4" position="float">
<label>Figure 4</label>
<caption><p>Prion protein vs. &#x03B1;-synuclein: current knowledge. Both proteins can undergo misfolding (1) which leads to the formation of different pathogenic strains (2). The pathogenic forms of both proteins can be transferred cell-to-cell (3) and spread from the periphery into the CNS <italic>in vivo</italic> (4). However, based on post-mortem data from α-synucleinopathy patients and in contrast to the prion protein, it is not clear how and where does &#x003B1;-synuclein pathology start and if the spreading observed in <italic>in vivo</italic> studies really happens in humans (4). Finally, unlike prion protein, no evidence of intraspecies or interpecies transmission of &#x003B1;-syn has ever been reported (5).</p></caption>
<graphic xlink:href="fnsyn-12-584536-g0004.tif"/>
</fig>
<p>However, there is evidence that challenges some of these observations and the prion hypothesis for &#x003B1;-syn (<xref ref-type="fig" rid="F4">Figure 4</xref>). On one hand, subsequent post-mortem studies showed that only half of PD cases present a pattern of Lewy pathology consistent with Braak&#x02019;s staging and that an important number do not even follow it (Kalaitzakis et al., <xref ref-type="bibr" rid="B126">2008</xref>; Jellinger, <xref ref-type="bibr" rid="B122">2009</xref>; Halliday et al., <xref ref-type="bibr" rid="B105">2012</xref>). In many cases, the distribution of &#x003B1;-syn inclusions is sparse and discrete, even at late stages of the disease (Beach et al., <xref ref-type="bibr" rid="B15">2009</xref>; Dijkstra et al., <xref ref-type="bibr" rid="B63">2014</xref>), and some patients do not show aggregates at all (Berg et al., <xref ref-type="bibr" rid="B23">2014</xref>). Moreover, no correlation has been observed between Braak&#x02019;s staging of Lewy pathology and severity of clinical progression (Jellinger, <xref ref-type="bibr" rid="B122">2009</xref>). In addition, cells within the same region are not equally affected by Lewy pathology, which is only observed in a small percentage of neurons, mainly affecting catecholaminergic and cholinergic but not GABAergic neurons. Furthermore, the strength of connectivity between brain areas does not correlate with Lewy pathology patterns (Surmeier et al., <xref ref-type="bibr" rid="B255">2017</xref>) and, in MSA, the trans-synaptic propagation of &#x003B1;-syn pathology proposed for PD cannot explain the spatial distribution of GCIs (Armstrong et al., <xref ref-type="bibr" rid="B9">2004</xref>; Dhillon et al., <xref ref-type="bibr" rid="B60">2019</xref>; Kaji et al., <xref ref-type="bibr" rid="B124">2020</xref>).</p>
<p>The ability of &#x003B1;-syn to propagate and generate aggregates in humans is also a matter of debate since additional transplantation studies did not show &#x003B1;-syn accumulation in the engrafted dopaminergic cells (Mendez et al., <xref ref-type="bibr" rid="B183">2008</xref>; Hallett et al., <xref ref-type="bibr" rid="B104">2014</xref>). Interestingly, the main difference between these studies and the ones showing Lewy pathology was the use of dissociated neurons instead of cellular aggregates or tissue pieces. Moreover, independently of the absence or presence of &#x003B1;-syn aggregates, transplanted neurons generally survive and remain healthy and functional for decades (Li et al., <xref ref-type="bibr" rid="B152">2016</xref>). The appearance of pathology in the engrafted cells has been, however, associated with an extensive microglial activation when cellular aggregates or tissue pieces are used (Kordower et al., <xref ref-type="bibr" rid="B137">2008</xref>; Li et al., <xref ref-type="bibr" rid="B151">2008</xref>). This effect was not observed when dissociated neurons were transplanted (Mendez et al., <xref ref-type="bibr" rid="B183">2008</xref>). Nevertheless, it is still unclear from where was the pathology observed in transplanted cells coming from, and why the number of neurons affected did not change with time (Kordower et al., <xref ref-type="bibr" rid="B137">2008</xref>; Li et al., <xref ref-type="bibr" rid="B151">2008</xref>, <xref ref-type="bibr" rid="B152">2016</xref>). It has been proposed that the graft&#x02019;s micro-environment together with the already stressed environment from the host may trigger the pathology in those cells (Surmeier et al., <xref ref-type="bibr" rid="B255">2017</xref>). In fact, post-mortem studies have shown that brain regions presenting &#x003B1;-syn inclusions do not necessarily develop neuronal loss, in contrast, neurodegeneration sometimes occurs in areas with no &#x003B1;-syn pathology or before it appears (Leak et al., <xref ref-type="bibr" rid="B143">2019</xref>). Furthermore, <italic>in vitro</italic> studies have shown that mutations in &#x003B1;-syn, such as A53E and G51D, which are associated with familiar forms of PD and MSA, attenuate aggregation and delay the pathology (Fares et al., <xref ref-type="bibr" rid="B76">2014</xref>; Ghosh et al., <xref ref-type="bibr" rid="B94">2014</xref>). Interestingly, different neuropathological reports have shown an absence of Lewy pathology in most patients with familiar forms of parkin-related PD and in a proportion of PD patients with mutations in the <italic>LRRK2</italic> gene, which are respectively the most common cause of recessive and dominant forms of PD, and a small proportion of sporadic PD cases (Kalia and Lang, <xref ref-type="bibr" rid="B127">2015</xref>; Tolosa et al., <xref ref-type="bibr" rid="B262">2020</xref>).</p>
<p>Bonafide prions can spread from extraneural sites into the CNS and the molecular processes underlying their spreading have been evaluated in detail (Kara et al., <xref ref-type="bibr" rid="B129">2018</xref>). Regarding &#x003B1;-syn, recent studies have demonstrated the presence of inclusions in peripheral sites, including cells of the enteric nervous system, nerve cells and fibers in the skin and submandibular salivary glands of &#x003B1;-synucleinopathies patients (Beach et al., <xref ref-type="bibr" rid="B17">2010</xref>, <xref ref-type="bibr" rid="B16">2016</xref>; Shannon et al., <xref ref-type="bibr" rid="B234">2012</xref>; Kim J. Y. et al., <xref ref-type="bibr" rid="B134">2019</xref>). Therefore, these data support the hypothesis that &#x003B1;-syn pathology may start in the periphery and ascend towards the CNS in a similar way to prions. In addition, it was reported that vagotomy reduces the risk of developing PD (Svensson et al., <xref ref-type="bibr" rid="B256">2015</xref>), that may be explained by a disruption of &#x003B1;-syn spreading from the periphery to the brain. However, these observations were not replicated in a different study with the same cohort but extended follow-up (Tysnes et al., <xref ref-type="bibr" rid="B267">2015</xref>). Therefore, the debate on the periphery as the possible initiation site of &#x003B1;-syn pathology remains unsolved, especially considering that: (i) &#x003B1;-syn is mainly expressed in the brain (Lashuel et al., <xref ref-type="bibr" rid="B140">2013</xref>); (ii) some peripheral regions with &#x003B1;-syn pathology do not present a clear exposure route, such as the cardiac sympathetic nerve (Orimo et al., <xref ref-type="bibr" rid="B192">2008</xref>); (iii) no cases have been found in post-mortem whole body studies with &#x003B1;-syn inclusions in the periphery without the brain being affected (Lionnet et al., <xref ref-type="bibr" rid="B156">2018</xref>); and (iv) peripheral &#x003B1;-syn aggregates from PD patients show lack of pathogenic potential (Recasens et al., <xref ref-type="bibr" rid="B218">2018</xref>; <xref ref-type="fig" rid="F4">Figure 4</xref>).</p>
<p>Other exogenous and endogenous factors may trigger the pathological changes underlying &#x003B1;-synucleinopathies and &#x003B1;-syn aggregation (<xref ref-type="fig" rid="F3">Figure 3</xref>). Thus, gut dysbiosis and microbiota have been associated with PD (Fitzgerald et al., <xref ref-type="bibr" rid="B81">2019</xref>). Moreover, recent studies demonstrated that amyloid proteins produced by gut bacteria can induce &#x003B1;-syn aggregation and seeding (Sampson et al., <xref ref-type="bibr" rid="B226">2016</xref>, <xref ref-type="bibr" rid="B225">2020</xref>), and that viral infection disrupts cellular proteostasis and causes &#x003B1;-syn aggregation (Marreiros et al., <xref ref-type="bibr" rid="B172">2020</xref>). Several authors have therefore suggested that neurodegeneration and the neurological deficits observed in &#x003B1;-synucleinopathies may be triggered by factors other than &#x003B1;-syn, like inflammation or local micro environmental conditions (Engelender and Isacson, <xref ref-type="bibr" rid="B70">2017</xref>) and that selective vulnerability of neuronal subpopulations may better explain the generation of &#x003B1;-syn inclusions throughout disease progression, rather than prion-like transmission (Surmeier et al., <xref ref-type="bibr" rid="B255">2017</xref>). In this regard, a protective role of &#x003B1;-syn aggregates has been suggested, where they may be a consequence of the disease process rather than the cause (Olanow et al., <xref ref-type="bibr" rid="B189">2004</xref>; Sian-Hulsmann et al., <xref ref-type="bibr" rid="B237">2015</xref>). Based on these observations, and the fact that severity of clinical symptoms correlates with neurodegeneration rather than with &#x003B1;-syn inclusions in humans (Beach et al., <xref ref-type="bibr" rid="B15">2009</xref>), the role of &#x003B1;-syn in these pathologies remains unclear.</p>
<p>It has to be mention that, to date, despite longitudinal studies with &#x003B1;-synucleinopathies patients have demonstrated clinical and biological changes throughout disease progression, they have not been able to show meaningful concordance between them, making difficult to properly define disease stages and, therefore, to evaluate the association between &#x003B1;-syn pathology and disease progression (Espay et al., <xref ref-type="bibr" rid="B72">2020</xref>). In addition to that, the absence of significant correlation between &#x003B1;-syn pathology and cell loss in brain areas affected in these disorders could be due to a lack of sensitivity of current immunohistochemical methods. Further studies evaluating the presence of &#x003B1;-syn oligomers or early aggregation stages by novel techniques such as AS-PLA, RT-QuIC or PMCA may lead to a better understanding of the role of &#x003B1;-syn in &#x003B1;-synucleinopathies and clarify the possible pathological routes of &#x003B1;-syn propagation (Bengoa-Vergniory et al., <xref ref-type="bibr" rid="B21">2017</xref>; Shahnawaz et al., <xref ref-type="bibr" rid="B233">2020</xref>).</p>
<p>Finally, no evidences of &#x003B1;-syn transmission between humans has ever been reported, including iatrogenic (Irwin et al., <xref ref-type="bibr" rid="B119">2013</xref>; Beekes et al., <xref ref-type="bibr" rid="B18">2014</xref>), and there is no epidemiological data supporting this possibility for any &#x003B1;-synucleinopathy (Rajput et al., <xref ref-type="bibr" rid="B217">2016</xref>; <xref ref-type="fig" rid="F4">Figure 4</xref>). No evidences of transmission from animal to human have been found either (Wenning et al., <xref ref-type="bibr" rid="B285">2018</xref>). Historically, prion infections have been a rarity whereas &#x003B1;-synucleinopathies present an important incidence that remains relatively stable over time in various ethnical populations (Pringsheim et al., <xref ref-type="bibr" rid="B213">2014</xref>; Leak et al., <xref ref-type="bibr" rid="B143">2019</xref>), however, <italic>in vivo</italic> studies show that the level of infectivity of &#x003B1;-syn aggregates per amount of protein might be orders of magnitude lower than that of prions (Watts, <xref ref-type="bibr" rid="B283">2019</xref>).</p>
<p>Overall, despite &#x003B1;-syn shares several characteristics with prions, the absence of infectivity, the lack of human studies supporting the hypothesis and the existence of contradictory data must be taken in consideration. Thus, the term &#x0201C;prionoid&#x0201D; has been proposed to designate proteins that share propagative mechanisms with prions but may not be transmissible between individuals (Kara et al., <xref ref-type="bibr" rid="B129">2018</xref>). At present, the most probable explanation regarding the start and progression of &#x003B1;-synucleionopathies would be that they are the consequence of a multifactorial process. This process would include the occurrence of exogenous and cellular micro-environmental changes in the affected regions that may trigger and modulate the pathology, and the presence of different &#x003B1;-syn strains that are able to spread through the organism in a cell type/susceptibility-dependent manner leading to different neuroanatomical spreading patterns.</p>
</sec>
<sec id="s5">
<title>Futures Perspectives in &#x003B1;-Syn Research and Therapy</title>
<p>Although our knowledge about &#x003B1;-syn, its physiological functions, structure, properties and its pathological role in &#x003B1;-synucleinopathies have been extensively studied, there are still gaps that must be filled to completely understand the nature and the importance of this protein.</p>
<p>The characterization of &#x003B1;-syn interactions in the different subcellular compartments, not only in the CNS, but also in peripheral organs may be essential to fully understand its functions, the cellular and systemic changes that underlie &#x003B1;-synucleinopathies, and the possible deleterious consequences of therapeutic strategies targeting &#x003B1;-syn. The combination of novel super-resolution imaging, proteomics and computational techniques constitute a powerful approach to define &#x003B1;-syn interactome (Br&#x000E1;s et al., <xref ref-type="bibr" rid="B31">2020</xref>). A complete and detailed identification of all &#x003B1;-syn PTM, the different pathways involved in its clearance and the role of glial cells in this process represent other important targets for further studies (Lopes Da Fonseca et al., <xref ref-type="bibr" rid="B159">2015</xref>; Gonzalez et al., <xref ref-type="bibr" rid="B98">2019</xref>; Tremblay et al., <xref ref-type="bibr" rid="B265">2019</xref>). Regarding the pathological role of &#x003B1;-syn, the absence of specific biomarkers and PET tracers constitute, at present, one of the most important disadvantages to identify its spatial and temporal contribution to disease progression in &#x003B1;-synucleinopathy patients. In addition, the biochemical composition and the molecular architecture of &#x003B1;-syn strains and inclusions and the cellular and environmental factors modulating their formation in the different disorders have not yet been completely revealed, mainly due to the lack of proper and highly sensitive protocols and tools. Elucidating the native conformation of &#x003B1;-syn and the different pathogenic strains by cryo-electron microscopy (Chen S. W. et al., <xref ref-type="bibr" rid="B45">2015</xref>; Li et al., <xref ref-type="bibr" rid="B149">2018</xref>; Guerrero-Ferreira et al., <xref ref-type="bibr" rid="B102">2019</xref>), nuclear magnetic resonance (Galvagnion et al., <xref ref-type="bibr" rid="B87">2019</xref>) or super-resolution imaging techniques (Nugent et al., <xref ref-type="bibr" rid="B188">2017</xref>; Shahmoradian et al., <xref ref-type="bibr" rid="B232">2019</xref>) will be essential to develop alternative drug-based disease modifying therapies. The establishment of brain banks of high-quality post-mortem brain tissue, CSF, plasma and fibroblast from clinically and pathologically well-defined patients and healthy controls will improve the potential of future studies. Moreover, the incorporation of induced-pluripotent stem cells (iPSCs) to those banks, to develop human patient-specific <italic>in vitro</italic> models of the disease, should be considered. Finally, further genetic and epigenetic studies will also provide important insights into the mechanism underlying &#x003B1;-synucleinopathies, the differences between them, as well as novel therapeutic targets.</p>
<p>Though the exact role of &#x003B1;-syn in the pathology has not yet been fully elucidated, an important number of preclinical studies and clinical trials have been focused on targeting directly &#x003B1;-syn and &#x003B1;-syn aggregation, or indirectly through the modulation of processes associated with its accumulation. The use of small molecules to target &#x003B1;-syn aggregation have shown positive results in preclinical models of &#x003B1;-synucleionopathies by reducing aggregation and accumulation of &#x003B1;-syn inclusions, neurodegeneration and motor symptoms (Finkelstein et al., <xref ref-type="bibr" rid="B80">2017</xref>; Price et al., <xref ref-type="bibr" rid="B212">2018</xref>; Heras-Garvin et al., <xref ref-type="bibr" rid="B109">2019</xref>; Wegrzynowicz et al., <xref ref-type="bibr" rid="B284">2019</xref>). Antibiotics such as rifampicin also reduces &#x003B1;-syn aggregation and fibrillization (Li et al., <xref ref-type="bibr" rid="B150">2004</xref>) and showed positive results in animal models (Ubhi et al., <xref ref-type="bibr" rid="B268">2008</xref>). Different preclinical studies have demonstrated that &#x003B1;-syn immunotherapy enhances &#x003B1;-syn clearance, prevents spreading and neuronal loss and demyelination and improves motor function in animal models (Masliah et al., <xref ref-type="bibr" rid="B175">2011</xref>; Mandler et al., <xref ref-type="bibr" rid="B168">2014</xref>, <xref ref-type="bibr" rid="B167">2015</xref>). Enhancing &#x003B1;-syn degradation by modulating cellular pathways and the activation of glial cell types associated with &#x003B1;-syn clearance constitute another promising strategy (Malagelada et al., <xref ref-type="bibr" rid="B165">2010</xref>; Gao et al., <xref ref-type="bibr" rid="B89">2019</xref>; Perrino et al., <xref ref-type="bibr" rid="B205">2019</xref>). Stimulation of microglial-dependent clearance of &#x003B1;-syn reduces the number of inclusions, ameliorates motor symptoms and shows a neuroprotective effect in <italic>in vivo</italic> models of MSA and PD (Park et al., <xref ref-type="bibr" rid="B198">2016</xref>; Venezia et al., <xref ref-type="bibr" rid="B274">2017</xref>; Choi et al., <xref ref-type="bibr" rid="B48">2020</xref>). Intriguingly, microglial activation and neuroinflammation can also promote &#x003B1;-syn aggregation and induce neurodegeneration, accelerating disease progression (Lema Tome et al., <xref ref-type="bibr" rid="B148">2013</xref>), therefore, reduction of microglial activation have also been used for disease modification (Liu et al., <xref ref-type="bibr" rid="B157">2019</xref>). Recently, the use of antisense nucleotides (ASO) to selectively inhibit proteins associated with &#x003B1;-syn pathology in specific brain regions or cell types has been proposed as an alternative approach to reduce &#x003B1;-syn accumulation in PD models (Zhao et al., <xref ref-type="bibr" rid="B293">2017</xref>; Alarc&#x000F3;n-Ar&#x000ED;s et al., <xref ref-type="bibr" rid="B3">2018</xref>). This is particularly important since altering or removing &#x003B1;-syn gene expression in previous studies has shown profound and deleterious intracellular and developmental effects that in some cases could induce neuronal loss (Perez and Hastings, <xref ref-type="bibr" rid="B204">2004</xref>; Benskey et al., <xref ref-type="bibr" rid="B22">2016</xref>).</p>
<p>Most of these therapeutic strategies are currently under evaluation in human clinical trials (Heras-Garvin and Stefanova, <xref ref-type="bibr" rid="B108">2020</xref>). Unfortunately, some of them have not shown ability to slow or halt disease progression (Heras-Garvin and Stefanova, <xref ref-type="bibr" rid="B108">2020</xref>). The distinct efficacies observed between preclinical studies, based on <italic>in vitro</italic> and <italic>in vivo</italic> models, and the data from human studies could be explained by the neurobiological differences among species, but may be a consequence of current limitations to recruit patients at early stages of the disease, when significant neurodegeneration and motor symptoms are not yet present, to misdiagnosis and to the absence of specific biomarkers for &#x003B1;-syn.</p>
</sec>
<sec id="s6">
<title>Conclusions</title>
<p>It has been a long journey since &#x003B1;-syn was discovered 30 years ago. Many <italic>in vitro</italic> and <italic>in vivo</italic> studies have contributed to a better understanding of this versatile and multifaceted protein, its functions and its potential role in neurodegeneration. Moreover, the analysis of human material has indeed supported the idea that &#x003B1;-syn may contribute in some extent to the pathogenic events underlying the &#x003B1;-synucleionopathies. However, whether &#x003B1;-syn is the cause or main force driving these disorders or a mere secondary event is still a matter of debate. The use of novel highly sensitive tools and techniques in future studies, combined with the recruitment and collection of human material from well-characterized and documented cohorts, will definitely help us to finally define the pathogenic role of &#x003B1;-syn and to improve the development of proper therapeutic strategies.</p>
</sec>
<sec id="s7">
<title>Author Contributions</title>
<p>AH-G: conception and design, drafting and revising the manuscript, and final approval of the submission. NS: conception and design, revising the manuscript, and final approval of the submission. All authors contributed to the article and approved the submitted version.</p>
</sec>
<sec id="s8">
<title>Conflict of Interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
</body>
<back>
<fn-group>
<fn fn-type="financial-disclosure">
<p><bold>Funding.</bold> This work was supported by a grant of the Austrian Science Funds (FWF) F4414 and the grant &#x0201C;Fit for Science&#x0201D; of the Tyrol County.</p>
</fn>
</fn-group>
<ref-list>
<title>References</title>
<ref id="B1"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Abdelmotilib</surname> <given-names>H.</given-names></name> <name><surname>Maltbie</surname> <given-names>T.</given-names></name> <name><surname>Delic</surname> <given-names>V.</given-names></name> <name><surname>Liu</surname> <given-names>Z.</given-names></name> <name><surname>Hu</surname> <given-names>X.</given-names></name> <name><surname>Fraser</surname> <given-names>K. B.</given-names></name> <etal/></person-group>. (<year>2017</year>). <article-title>&#x003B1;-Synuclein fibril-induced inclusion spread in rats and mice correlates with dopaminergic Neurodegeneration</article-title>. <source>Neurobiol. Dis.</source> <volume>105</volume>, <fpage>84</fpage>&#x02013;<lpage>98</lpage>. <pub-id pub-id-type="doi">10.1016/j.nbd.2017.05.014</pub-id><pub-id pub-id-type="pmid">28576704</pub-id></citation></ref>
<ref id="B2"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Alam</surname> <given-names>P.</given-names></name> <name><surname>Bousset</surname> <given-names>L.</given-names></name> <name><surname>Melki</surname> <given-names>R.</given-names></name> <name><surname>Otzen</surname> <given-names>D. E.</given-names></name></person-group> (<year>2019</year>). <article-title>&#x003B1;-synuclein oligomers and fibrils: a spectrum of species, a spectrum of toxicities</article-title>. <source>J. Neurochem.</source> <volume>150</volume>, <fpage>522</fpage>&#x02013;<lpage>534</lpage>. <pub-id pub-id-type="doi">10.1111/jnc.14808</pub-id><pub-id pub-id-type="pmid">31254394</pub-id></citation></ref>
<ref id="B3"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Alarc&#x000F3;n-Ar&#x000ED;s</surname> <given-names>D.</given-names></name> <name><surname>Recasens</surname> <given-names>A.</given-names></name> <name><surname>Galofre</surname> <given-names>M.</given-names></name> <name><surname>Carballo-Carbajal</surname> <given-names>I.</given-names></name> <name><surname>Zacchi</surname> <given-names>N.</given-names></name> <name><surname>Ruiz-Bronchal</surname> <given-names>E.</given-names></name> <etal/></person-group>. (<year>2018</year>). <article-title>Selective &#x003B1;-synuclein knockdown in monoamine neurons by intranasal oligonucleotide delivery: potential therapy for Parkinson&#x02019;s disease</article-title>. <source>Mol. Ther.</source> <volume>26</volume>, <fpage>550</fpage>&#x02013;<lpage>567</lpage>. <pub-id pub-id-type="doi">10.1016/j.ymthe.2017.11.015</pub-id><pub-id pub-id-type="pmid">29273501</pub-id></citation></ref>
<ref id="B4"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Almandoz-Gil</surname> <given-names>L.</given-names></name> <name><surname>Persson</surname> <given-names>E.</given-names></name> <name><surname>Lindstrom</surname> <given-names>V.</given-names></name> <name><surname>Ingelsson</surname> <given-names>M.</given-names></name> <name><surname>Erlandsson</surname> <given-names>A.</given-names></name> <name><surname>Bergstrom</surname> <given-names>J.</given-names></name></person-group> (<year>2018</year>). <article-title><italic>In situ</italic> proximity ligation assay reveals co-localization of &#x003B1;-synuclein and SNARE proteins in murine primary neurons</article-title>. <source>Front. Neurol.</source> <volume>9</volume>:<fpage>180</fpage>. <pub-id pub-id-type="doi">10.3389/fneur.2018.00180</pub-id><pub-id pub-id-type="pmid">29623065</pub-id></citation></ref>
<ref id="B5"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Al-Wandi</surname> <given-names>A.</given-names></name> <name><surname>Ninkina</surname> <given-names>N.</given-names></name> <name><surname>Millership</surname> <given-names>S.</given-names></name> <name><surname>Williamson</surname> <given-names>S. J.</given-names></name> <name><surname>Jones</surname> <given-names>P. A.</given-names></name> <name><surname>Buchman</surname> <given-names>V. L.</given-names></name></person-group> (<year>2010</year>). <article-title>Absence of &#x003B1;-synuclein affects dopamine metabolism and synaptic markers in the striatum of aging mice</article-title>. <source>Neurobiol. Aging</source> <volume>31</volume>, <fpage>796</fpage>&#x02013;<lpage>804</lpage>. <pub-id pub-id-type="doi">10.1016/j.neurobiolaging.2008.11.001</pub-id><pub-id pub-id-type="pmid">19097673</pub-id></citation></ref>
<ref id="B6"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Angelova</surname> <given-names>P. R.</given-names></name> <name><surname>Ludtmann</surname> <given-names>M. H.</given-names></name> <name><surname>Horrocks</surname> <given-names>M. H.</given-names></name> <name><surname>Negoda</surname> <given-names>A.</given-names></name> <name><surname>Cremades</surname> <given-names>N.</given-names></name> <name><surname>Klenerman</surname> <given-names>D.</given-names></name> <etal/></person-group>. (<year>2016</year>). <article-title>Ca<sup>2+</sup> is a key factor in &#x003B1;-synuclein-induced neurotoxicity</article-title>. <source>J. Cell Sci.</source> <volume>129</volume>, <fpage>1792</fpage>&#x02013;<lpage>1801</lpage>. <pub-id pub-id-type="doi">10.1242/jcs.180737</pub-id><pub-id pub-id-type="pmid">26989132</pub-id></citation></ref>
<ref id="B7"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Arai</surname> <given-names>K.</given-names></name> <name><surname>Kato</surname> <given-names>N.</given-names></name> <name><surname>Kashiwado</surname> <given-names>K.</given-names></name> <name><surname>Hattori</surname> <given-names>T.</given-names></name></person-group> (<year>2000</year>). <article-title>Pure autonomic failure in association with human &#x003B1;-synucleinopathy</article-title>. <source>Neurosci. Lett.</source> <volume>296</volume>, <fpage>171</fpage>&#x02013;<lpage>173</lpage>. <pub-id pub-id-type="doi">10.1016/s0304-3940(00)01623-2</pub-id><pub-id pub-id-type="pmid">11109008</pub-id></citation></ref>
<ref id="B8"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Arawaka</surname> <given-names>S.</given-names></name> <name><surname>Sato</surname> <given-names>H.</given-names></name> <name><surname>Sasaki</surname> <given-names>A.</given-names></name> <name><surname>Koyama</surname> <given-names>S.</given-names></name> <name><surname>Kato</surname> <given-names>T.</given-names></name></person-group> (<year>2017</year>). <article-title>Mechanisms underlying extensive Ser129-phosphorylation in &#x003B1;-synuclein aggregates</article-title>. <source>Acta Neuropathol. Commun.</source> <volume>5</volume>:<fpage>48</fpage>. <pub-id pub-id-type="doi">10.1186/s40478-017-0452-6</pub-id><pub-id pub-id-type="pmid">28619113</pub-id></citation></ref>
<ref id="B9"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Armstrong</surname> <given-names>R. A.</given-names></name> <name><surname>Lantos</surname> <given-names>P. L.</given-names></name> <name><surname>Cairns</surname> <given-names>N. J.</given-names></name></person-group> (<year>2004</year>). <article-title>Spatial patterns of &#x003B1;-synuclein positive glial cytoplasmic inclusions in multiple system atrophy</article-title>. <source>Mov. Disord.</source> <volume>19</volume>, <fpage>109</fpage>&#x02013;<lpage>112</lpage>. <pub-id pub-id-type="doi">10.1002/mds.10637</pub-id><pub-id pub-id-type="pmid">14743371</pub-id></citation></ref>
<ref id="B10"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Austin</surname> <given-names>S. A.</given-names></name> <name><surname>Floden</surname> <given-names>A. M.</given-names></name> <name><surname>Murphy</surname> <given-names>E. J.</given-names></name> <name><surname>Combs</surname> <given-names>C. K.</given-names></name></person-group> (<year>2006</year>). <article-title>&#x003B1;-synuclein expression modulates microglial activation phenotype</article-title>. <source>J. Neurosci.</source> <volume>26</volume>, <fpage>10558</fpage>&#x02013;<lpage>10563</lpage>. <pub-id pub-id-type="doi">10.1523/JNEUROSCI.1799-06.2006</pub-id><pub-id pub-id-type="pmid">17035541</pub-id></citation></ref>
<ref id="B11"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Barber</surname> <given-names>T. R.</given-names></name> <name><surname>Lawton</surname> <given-names>M.</given-names></name> <name><surname>Rolinski</surname> <given-names>M.</given-names></name> <name><surname>Evetts</surname> <given-names>S.</given-names></name> <name><surname>Baig</surname> <given-names>F.</given-names></name> <name><surname>Ruffmann</surname> <given-names>C.</given-names></name> <etal/></person-group>. (<year>2017</year>). <article-title>Prodromal Parkinsonism and neurodegenerative risk stratification in REM sleep behavior disorder</article-title>. <source>Sleep</source> <volume>40</volume>:<fpage>zsx071</fpage>. <pub-id pub-id-type="doi">10.1093/sleep/zsx071</pub-id><pub-id pub-id-type="pmid">28472425</pub-id></citation></ref>
<ref id="B12"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Barbour</surname> <given-names>R.</given-names></name> <name><surname>Kling</surname> <given-names>K.</given-names></name> <name><surname>Anderson</surname> <given-names>J. P.</given-names></name> <name><surname>Banducci</surname> <given-names>K.</given-names></name> <name><surname>Cole</surname> <given-names>T.</given-names></name> <name><surname>Diep</surname> <given-names>L.</given-names></name> <etal/></person-group>. (<year>2008</year>). <article-title>Red blood cells are the major source of &#x003B1;-synuclein in blood</article-title>. <source>Neurodegener. Dis.</source> <volume>5</volume>, <fpage>55</fpage>&#x02013;<lpage>59</lpage>. <pub-id pub-id-type="doi">10.1159/000112832</pub-id><pub-id pub-id-type="pmid">18182779</pub-id></citation></ref>
<ref id="B13"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Bartels</surname> <given-names>T.</given-names></name> <name><surname>Choi</surname> <given-names>J. G.</given-names></name> <name><surname>Selkoe</surname> <given-names>D. J.</given-names></name></person-group> (<year>2011</year>). <article-title>&#x003B1;-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation</article-title>. <source>Nature</source> <volume>477</volume>, <fpage>107</fpage>&#x02013;<lpage>110</lpage>. <pub-id pub-id-type="doi">10.1038/nature10324</pub-id><pub-id pub-id-type="pmid">21841800</pub-id></citation></ref>
<ref id="B14"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Bassil</surname> <given-names>F.</given-names></name> <name><surname>Brown</surname> <given-names>H. J.</given-names></name> <name><surname>Pattabhiraman</surname> <given-names>S.</given-names></name> <name><surname>Iwasyk</surname> <given-names>J. E.</given-names></name> <name><surname>Maghames</surname> <given-names>C. M.</given-names></name> <name><surname>Meymand</surname> <given-names>E. S.</given-names></name> <etal/></person-group>. (<year>2020</year>). <article-title>Amyloid-&#x003B2; (A&#x003B2;) plaques promote seeding and spreading of &#x003B1;-synuclein and tau in a mouse model of Lewy body disorders with A&#x003B2; pathology</article-title>. <source>Neuron</source> <volume>105</volume>, <fpage>260.e6</fpage>&#x02013;<lpage>275.e6</lpage>. <pub-id pub-id-type="doi">10.1016/j.neuron.2019.10.010</pub-id><pub-id pub-id-type="pmid">31759806</pub-id></citation></ref>
<ref id="B15"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Beach</surname> <given-names>T. G.</given-names></name> <name><surname>Adler</surname> <given-names>C. H.</given-names></name> <name><surname>Lue</surname> <given-names>L.</given-names></name> <name><surname>Sue</surname> <given-names>L. I.</given-names></name> <name><surname>Bachalakuri</surname> <given-names>J.</given-names></name> <name><surname>Henry-Watson</surname> <given-names>J.</given-names></name> <etal/></person-group>. (<year>2009</year>). <article-title>Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction</article-title>. <source>Acta Neuropathol.</source> <volume>117</volume>, <fpage>613</fpage>&#x02013;<lpage>634</lpage>. <pub-id pub-id-type="doi">10.1007/s00401-009-0538-8</pub-id><pub-id pub-id-type="pmid">19399512</pub-id></citation></ref>
<ref id="B16"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Beach</surname> <given-names>T. G.</given-names></name> <name><surname>Adler</surname> <given-names>C. H.</given-names></name> <name><surname>Serrano</surname> <given-names>G.</given-names></name> <name><surname>Sue</surname> <given-names>L. I.</given-names></name> <name><surname>Walker</surname> <given-names>D. G.</given-names></name> <name><surname>Dugger</surname> <given-names>B. N.</given-names></name> <etal/></person-group>. (<year>2016</year>). <article-title>Prevalence of submandibular gland synucleinopathy in Parkinson&#x02019;s disease, dementia with Lewy bodies and other Lewy body disorders</article-title>. <source>J. Parkinsons Dis.</source> <volume>6</volume>, <fpage>153</fpage>&#x02013;<lpage>163</lpage>. <pub-id pub-id-type="doi">10.3233/JPD-150680</pub-id><pub-id pub-id-type="pmid">26756744</pub-id></citation></ref>
<ref id="B17"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Beach</surname> <given-names>T. G.</given-names></name> <name><surname>Adler</surname> <given-names>C. H.</given-names></name> <name><surname>Sue</surname> <given-names>L. I.</given-names></name> <name><surname>Vedders</surname> <given-names>L.</given-names></name> <name><surname>Lue</surname> <given-names>L.</given-names></name> <name><surname>White Iii</surname> <given-names>C. L.</given-names></name> <etal/></person-group>. (<year>2010</year>). <article-title>Multi-organ distribution of phosphorylated &#x003B1;-synuclein histopathology in subjects with Lewy body disorders</article-title>. <source>Acta Neuropathol.</source> <volume>119</volume>, <fpage>689</fpage>&#x02013;<lpage>702</lpage>. <pub-id pub-id-type="doi">10.1007/s00401-010-0664-3</pub-id><pub-id pub-id-type="pmid">20306269</pub-id></citation></ref>
<ref id="B18"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Beekes</surname> <given-names>M.</given-names></name> <name><surname>Thomzig</surname> <given-names>A.</given-names></name> <name><surname>Schulz-Schaeffer</surname> <given-names>W. J.</given-names></name> <name><surname>Burger</surname> <given-names>R.</given-names></name></person-group> (<year>2014</year>). <article-title>Is there a risk of prion-like disease transmission by Alzheimer- or Parkinson-associated protein particles?</article-title> <source>Acta Neuropathol.</source> <volume>128</volume>, <fpage>463</fpage>&#x02013;<lpage>476</lpage>. <pub-id pub-id-type="doi">10.1007/s00401-014-1324-9</pub-id><pub-id pub-id-type="pmid">25073522</pub-id></citation></ref>
<ref id="B20"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Bendor</surname> <given-names>J. T.</given-names></name> <name><surname>Logan</surname> <given-names>T. P.</given-names></name> <name><surname>Edwards</surname> <given-names>R. H.</given-names></name></person-group> (<year>2013</year>). <article-title>The function of &#x003B1;-synuclein</article-title>. <source>Neuron</source> <volume>79</volume>, <fpage>1044</fpage>&#x02013;<lpage>1066</lpage>. <pub-id pub-id-type="doi">10.1016/j.neuron.2013.09.004</pub-id><pub-id pub-id-type="pmid">24050397</pub-id></citation></ref>
<ref id="B19"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ben Gedalya</surname> <given-names>T.</given-names></name> <name><surname>Loeb</surname> <given-names>V.</given-names></name> <name><surname>Israeli</surname> <given-names>E.</given-names></name> <name><surname>Altschuler</surname> <given-names>Y.</given-names></name> <name><surname>Selkoe</surname> <given-names>D. J.</given-names></name> <name><surname>Sharon</surname> <given-names>R.</given-names></name></person-group> (<year>2009</year>). <article-title>&#x003B1;-synuclein and polyunsaturated fatty acids promote clathrin-mediated endocytosis and synaptic vesicle recycling</article-title>. <source>Traffic</source> <volume>10</volume>, <fpage>218</fpage>&#x02013;<lpage>234</lpage>. <pub-id pub-id-type="doi">10.1111/j.1600-0854.2008.00853.x</pub-id><pub-id pub-id-type="pmid">18980610</pub-id></citation></ref>
<ref id="B21"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Bengoa-Vergniory</surname> <given-names>N.</given-names></name> <name><surname>Roberts</surname> <given-names>R. F.</given-names></name> <name><surname>Wade-Martins</surname> <given-names>R.</given-names></name> <name><surname>Alegre-Abarrategui</surname> <given-names>J.</given-names></name></person-group> (<year>2017</year>). <article-title>&#x003B1;-synuclein oligomers: a new hope</article-title>. <source>Acta Neuropathol.</source> <volume>134</volume>, <fpage>819</fpage>&#x02013;<lpage>838</lpage>. <pub-id pub-id-type="doi">10.1007/s00401-017-1755-1</pub-id><pub-id pub-id-type="pmid">28803412</pub-id></citation></ref>
<ref id="B22"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Benskey</surname> <given-names>M. J.</given-names></name> <name><surname>Perez</surname> <given-names>R. G.</given-names></name> <name><surname>Manfredsson</surname> <given-names>F. P.</given-names></name></person-group> (<year>2016</year>). <article-title>The contribution of &#x003B1;-synuclein to neuronal survival and function&#x02014;implications for Parkinson&#x02019;s disease</article-title>. <source>J. Neurochem.</source> <volume>137</volume>, <fpage>331</fpage>&#x02013;<lpage>359</lpage>. <pub-id pub-id-type="doi">10.1111/jnc.13570</pub-id><pub-id pub-id-type="pmid">26852372</pub-id></citation></ref>
<ref id="B23"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Berg</surname> <given-names>D.</given-names></name> <name><surname>Postuma</surname> <given-names>R. B.</given-names></name> <name><surname>Bloem</surname> <given-names>B.</given-names></name> <name><surname>Chan</surname> <given-names>P.</given-names></name> <name><surname>Dubois</surname> <given-names>B.</given-names></name> <name><surname>Gasser</surname> <given-names>T.</given-names></name> <etal/></person-group>. (<year>2014</year>). <article-title>Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson&#x02019;s disease</article-title>. <source>Mov. Disord.</source> <volume>29</volume>, <fpage>454</fpage>&#x02013;<lpage>462</lpage>. <pub-id pub-id-type="doi">10.1002/mds.25844</pub-id><pub-id pub-id-type="pmid">24619848</pub-id></citation></ref>
<ref id="B24"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Binolfi</surname> <given-names>A.</given-names></name> <name><surname>Theillet</surname> <given-names>F. X.</given-names></name> <name><surname>Selenko</surname> <given-names>P.</given-names></name></person-group> (<year>2012</year>). <article-title>Bacterial in-cell NMR of human &#x003B1;-synuclein: a disordered monomer by nature?</article-title> <source>Biochem. Soc. Trans.</source> <volume>40</volume>, <fpage>950</fpage>&#x02013;<lpage>954</lpage>. <pub-id pub-id-type="doi">10.1042/bst20120096</pub-id><pub-id pub-id-type="pmid">22988846</pub-id></citation></ref>
<ref id="B25"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Bousset</surname> <given-names>L.</given-names></name> <name><surname>Pieri</surname> <given-names>L.</given-names></name> <name><surname>Ruiz-Arlandis</surname> <given-names>G.</given-names></name> <name><surname>Gath</surname> <given-names>J.</given-names></name> <name><surname>Jensen</surname> <given-names>P. H.</given-names></name> <name><surname>Habenstein</surname> <given-names>B.</given-names></name> <etal/></person-group>. (<year>2013</year>). <article-title>Structural and functional characterization of two &#x003B1;-synuclein strains</article-title>. <source>Nat. Commun.</source> <volume>4</volume>:<fpage>2575</fpage>. <pub-id pub-id-type="doi">10.3990/1.9789036529310</pub-id><pub-id pub-id-type="pmid">24108358</pub-id></citation></ref>
<ref id="B27"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Braak</surname> <given-names>H.</given-names></name> <name><surname>Del Tredici</surname> <given-names>K.</given-names></name> <name><surname>Rub</surname> <given-names>U.</given-names></name> <name><surname>De Vos</surname> <given-names>R. A.</given-names></name> <name><surname>Jansen Steur</surname> <given-names>E. N.</given-names></name> <name><surname>Braak</surname> <given-names>E.</given-names></name></person-group> (<year>2003a</year>). <article-title>Staging of brain pathology related to sporadic Parkinson&#x02019;s disease</article-title>. <source>Neurobiol. Aging</source> <volume>24</volume>, <fpage>197</fpage>&#x02013;<lpage>211</lpage>. <pub-id pub-id-type="doi">10.1016/s0197-4580(02)00065-9</pub-id><pub-id pub-id-type="pmid">12498954</pub-id></citation></ref>
<ref id="B29"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Braak</surname> <given-names>H.</given-names></name> <name><surname>R&#x000FC;b</surname> <given-names>U.</given-names></name> <name><surname>Gai</surname> <given-names>W. P.</given-names></name> <name><surname>Del Tredici</surname> <given-names>K.</given-names></name></person-group> (<year>2003b</year>). <article-title>Idiopathic Parkinson&#x02019;s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen</article-title>. <source>J. Neural Transm.</source> <volume>110</volume>, <fpage>517</fpage>&#x02013;<lpage>536</lpage>. <pub-id pub-id-type="doi">10.1007/s00702-002-0808-2</pub-id><pub-id pub-id-type="pmid">12721813</pub-id></citation></ref>
<ref id="B26"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Braak</surname> <given-names>H.</given-names></name> <name><surname>De Vos</surname> <given-names>R. A.</given-names></name> <name><surname>Bohl</surname> <given-names>J.</given-names></name> <name><surname>Del Tredici</surname> <given-names>K.</given-names></name></person-group> (<year>2006</year>). <article-title>Gastric &#x003B1;-synuclein immunoreactive inclusions in Meissner&#x02019;s and Auerbach&#x02019;s plexuses in cases staged for Parkinson&#x02019;s disease-related brain pathology</article-title>. <source>Neurosci. Lett.</source> <volume>396</volume>, <fpage>67</fpage>&#x02013;<lpage>72</lpage>. <pub-id pub-id-type="doi">10.1016/j.neulet.2005.11.012</pub-id><pub-id pub-id-type="pmid">16330147</pub-id></citation></ref>
<ref id="B28"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Braak</surname> <given-names>H.</given-names></name> <name><surname>Ghebremedhin</surname> <given-names>E.</given-names></name> <name><surname>Rub</surname> <given-names>U.</given-names></name> <name><surname>Bratzke</surname> <given-names>H.</given-names></name> <name><surname>Del Tredici</surname> <given-names>K.</given-names></name></person-group> (<year>2004</year>). <article-title>Stages in the development of Parkinson&#x02019;s disease-related pathology</article-title>. <source>Cell Tissue Res.</source> <volume>318</volume>, <fpage>121</fpage>&#x02013;<lpage>134</lpage>. <pub-id pub-id-type="doi">10.1007/s00441-004-0956-9</pub-id><pub-id pub-id-type="pmid">15338272</pub-id></citation></ref>
<ref id="B30"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Braak</surname> <given-names>H.</given-names></name> <name><surname>Sastre</surname> <given-names>M.</given-names></name> <name><surname>Bohl</surname> <given-names>J. R.</given-names></name> <name><surname>De Vos</surname> <given-names>R. A.</given-names></name> <name><surname>Del Tredici</surname> <given-names>K.</given-names></name></person-group> (<year>2007</year>). <article-title>Parkinson&#x02019;s disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons</article-title>. <source>Acta Neuropathol.</source> <volume>113</volume>, <fpage>421</fpage>&#x02013;<lpage>429</lpage>. <pub-id pub-id-type="doi">10.1007/s00401-007-0193-x</pub-id><pub-id pub-id-type="pmid">17294202</pub-id></citation></ref>
<ref id="B31"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Br&#x000E1;s</surname> <given-names>I. C.</given-names></name> <name><surname>Dominguez-Meijide</surname> <given-names>A.</given-names></name> <name><surname>Gerhardt</surname> <given-names>E.</given-names></name> <name><surname>Koss</surname> <given-names>D.</given-names></name> <name><surname>Lazaro</surname> <given-names>D. F.</given-names></name> <name><surname>Santos</surname> <given-names>P. I.</given-names></name> <etal/></person-group>. (<year>2020</year>). <article-title>Synucleinopathies: where we are and where we need to go</article-title>. <source>J. Neurochem.</source> <volume>153</volume>, <fpage>433</fpage>&#x02013;<lpage>454</lpage>. <pub-id pub-id-type="doi">10.1111/jnc.14965</pub-id><pub-id pub-id-type="pmid">31957016</pub-id></citation></ref>
<ref id="B32"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Bridi</surname> <given-names>J. C.</given-names></name> <name><surname>Hirth</surname> <given-names>F.</given-names></name></person-group> (<year>2018</year>). <article-title>Mechanisms of &#x003B1;-synuclein induced synaptopathy in Parkinson&#x02019;s disease</article-title>. <source>Front. Neurosci.</source> <volume>12</volume>:<fpage>80</fpage>. <pub-id pub-id-type="doi">10.3389/fnins.2018.00080</pub-id><pub-id pub-id-type="pmid">29515354</pub-id></citation></ref>
<ref id="B33"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Brochard</surname> <given-names>V.</given-names></name> <name><surname>Combadi&#x000E8;re</surname> <given-names>B.</given-names></name> <name><surname>Prigent</surname> <given-names>A.</given-names></name> <name><surname>Laouar</surname> <given-names>Y.</given-names></name> <name><surname>Perrin</surname> <given-names>A.</given-names></name> <name><surname>Beray-Berthat</surname> <given-names>V.</given-names></name> <etal/></person-group>. (<year>2009</year>). <article-title>Infiltration of CD4<sup>+</sup> lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease</article-title>. <source>J. Clin. Invest.</source> <volume>119</volume>, <fpage>182</fpage>&#x02013;<lpage>192</lpage>. <pub-id pub-id-type="doi">10.1172/JCI36470</pub-id><pub-id pub-id-type="pmid">19104149</pub-id></citation></ref>
<ref id="B34"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Brundin</surname> <given-names>P.</given-names></name> <name><surname>Li</surname> <given-names>J. Y.</given-names></name> <name><surname>Holton</surname> <given-names>J. L.</given-names></name> <name><surname>Lindvall</surname> <given-names>O.</given-names></name> <name><surname>Revesz</surname> <given-names>T.</given-names></name></person-group> (<year>2008</year>). <article-title>Research in motion: the enigma of Parkinson&#x02019;s disease pathology spread</article-title>. <source>Nat. Rev. Neurosci.</source> <volume>9</volume>, <fpage>741</fpage>&#x02013;<lpage>745</lpage>. <pub-id pub-id-type="doi">10.1038/nrn2477</pub-id><pub-id pub-id-type="pmid">18769444</pub-id></citation></ref>
<ref id="B35"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Buell</surname> <given-names>A. K.</given-names></name> <name><surname>Galvagnion</surname> <given-names>C.</given-names></name> <name><surname>Gaspar</surname> <given-names>R.</given-names></name> <name><surname>Sparr</surname> <given-names>E.</given-names></name> <name><surname>Vendruscolo</surname> <given-names>M.</given-names></name> <name><surname>Knowles</surname> <given-names>T. P.</given-names></name> <etal/></person-group>. (<year>2014</year>). <article-title>Solution conditions determine the relative importance of nucleation and growth processes in &#x003B1;-synuclein aggregation</article-title>. <source>Proc. Natl. Acad. Sci. U S A</source> <volume>111</volume>, <fpage>7671</fpage>&#x02013;<lpage>7676</lpage>. <pub-id pub-id-type="doi">10.1073/pnas.1315346111</pub-id><pub-id pub-id-type="pmid">24817693</pub-id></citation></ref>
<ref id="B36"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Burr&#x000E9;</surname> <given-names>J.</given-names></name> <name><surname>Sharma</surname> <given-names>M.</given-names></name> <name><surname>Sudhof</surname> <given-names>T. C.</given-names></name></person-group> (<year>2018</year>). <article-title>Cell biology and pathophysiology of &#x003B1;-synuclein</article-title>. <source>Cold Spring Harb. Perspect. Med.</source> <volume>8</volume>:<fpage>a024091</fpage>. <pub-id pub-id-type="doi">10.1101/cshperspect.a024091</pub-id><pub-id pub-id-type="pmid">28108534</pub-id></citation></ref>
<ref id="B37"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Burr&#x000E9;</surname> <given-names>J.</given-names></name> <name><surname>Sharma</surname> <given-names>M.</given-names></name> <name><surname>Tsetsenis</surname> <given-names>T.</given-names></name> <name><surname>Buchman</surname> <given-names>V.</given-names></name> <name><surname>Etherton</surname> <given-names>M. R.</given-names></name> <name><surname>Sudhof</surname> <given-names>T. C.</given-names></name></person-group> (<year>2010</year>). <article-title>&#x003B1;-synuclein promotes SNARE-complex assembly <italic>in vivo</italic> and <italic>in vitro</italic></article-title>. <source>Science</source> <volume>329</volume>, <fpage>1663</fpage>&#x02013;<lpage>1667</lpage>. <pub-id pub-id-type="doi">10.1126/science.1195227</pub-id><pub-id pub-id-type="pmid">20798282</pub-id></citation></ref>
<ref id="B38"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Burr&#x000E9;</surname> <given-names>J.</given-names></name> <name><surname>Vivona</surname> <given-names>S.</given-names></name> <name><surname>Diao</surname> <given-names>J.</given-names></name> <name><surname>Sharma</surname> <given-names>M.</given-names></name> <name><surname>Brunger</surname> <given-names>A. T.</given-names></name> <name><surname>Sudhof</surname> <given-names>T. C.</given-names></name></person-group> (<year>2013</year>). <article-title>Properties of native brain &#x003B1;-synuclein</article-title>. <source>Nature</source> <volume>498</volume>, <fpage>E4</fpage>&#x02013;<lpage>6</lpage>; discussion <fpage>E6</fpage>&#x02013;<lpage>E7</lpage>. <pub-id pub-id-type="doi">10.1038/nature12125</pub-id><pub-id pub-id-type="pmid">23765500</pub-id></citation></ref>
<ref id="B39"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Butkovich</surname> <given-names>L. M.</given-names></name> <name><surname>Houser</surname> <given-names>M. C.</given-names></name> <name><surname>Tansey</surname> <given-names>M. G.</given-names></name></person-group> (<year>2018</year>). <article-title>&#x003B1;-synuclein and noradrenergic modulation of immune cells in Parkinson&#x02019;s disease pathogenesis</article-title>. <source>Front. Neurosci.</source> <volume>12</volume>:<fpage>626</fpage>. <pub-id pub-id-type="doi">10.3389/fnins.2018.00626</pub-id><pub-id pub-id-type="pmid">30258347</pub-id></citation></ref>
<ref id="B40"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Candelise</surname> <given-names>N.</given-names></name> <name><surname>Schmitz</surname> <given-names>M.</given-names></name> <name><surname>Llorens</surname> <given-names>F.</given-names></name> <name><surname>Villar-Pique</surname> <given-names>A.</given-names></name> <name><surname>Cramm</surname> <given-names>M.</given-names></name> <name><surname>Thom</surname> <given-names>T.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>Seeding variability of different &#x003B1;-synuclein strains in synucleinopathies</article-title>. <source>Ann. Neurol.</source> <volume>85</volume>, <fpage>691</fpage>&#x02013;<lpage>703</lpage>. <pub-id pub-id-type="doi">10.1002/ana.25446</pub-id><pub-id pub-id-type="pmid">30805957</pub-id></citation></ref>
<ref id="B41"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Candelise</surname> <given-names>N.</given-names></name> <name><surname>Schmitz</surname> <given-names>M.</given-names></name> <name><surname>Thune</surname> <given-names>K.</given-names></name> <name><surname>Cramm</surname> <given-names>M.</given-names></name> <name><surname>Rabano</surname> <given-names>A.</given-names></name> <name><surname>Zafar</surname> <given-names>S.</given-names></name> <etal/></person-group>. (<year>2020</year>). <article-title>Effect of the micro-environment on &#x003B1;-synuclein conversion and implication in seeded conversion assays</article-title>. <source>Transl. Neurodegener.</source> <volume>9</volume>:<fpage>5</fpage>. <pub-id pub-id-type="doi">10.1186/s40035-019-0181-9</pub-id><pub-id pub-id-type="pmid">31988747</pub-id></citation></ref>
<ref id="B42"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Cappai</surname> <given-names>R.</given-names></name> <name><surname>Leck</surname> <given-names>S. L.</given-names></name> <name><surname>Tew</surname> <given-names>D. J.</given-names></name> <name><surname>Williamson</surname> <given-names>N. A.</given-names></name> <name><surname>Smith</surname> <given-names>D. P.</given-names></name> <name><surname>Galatis</surname> <given-names>D.</given-names></name> <etal/></person-group>. (<year>2005</year>). <article-title>Dopamine promotes &#x003B1;-synuclein aggregation into SDS-resistant soluble oligomers <italic>via</italic> a distinct folding pathway</article-title>. <source>FASEB J.</source> <volume>19</volume>, <fpage>1377</fpage>&#x02013;<lpage>1379</lpage>. <pub-id pub-id-type="doi">10.1096/fj.04-3437fje</pub-id><pub-id pub-id-type="pmid">15946991</pub-id></citation></ref>
<ref id="B43"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Challis</surname> <given-names>C.</given-names></name> <name><surname>Hori</surname> <given-names>A.</given-names></name> <name><surname>Sampson</surname> <given-names>T. R.</given-names></name> <name><surname>Yoo</surname> <given-names>B. B.</given-names></name> <name><surname>Challis</surname> <given-names>R. C.</given-names></name> <name><surname>Hamilton</surname> <given-names>A. M.</given-names></name> <etal/></person-group>. (<year>2020</year>). <article-title>Gut-seeded &#x003B1;-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice</article-title>. <source>Nat. Neurosci.</source> <volume>23</volume>, <fpage>327</fpage>&#x02013;<lpage>336</lpage>. <pub-id pub-id-type="doi">10.1038/s41593-020-0589-7</pub-id><pub-id pub-id-type="pmid">32066981</pub-id></citation></ref>
<ref id="B44"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Chandra</surname> <given-names>S.</given-names></name> <name><surname>Chen</surname> <given-names>X.</given-names></name> <name><surname>Rizo</surname> <given-names>J.</given-names></name> <name><surname>Jahn</surname> <given-names>R.</given-names></name> <name><surname>Sudhof</surname> <given-names>T. C.</given-names></name></person-group> (<year>2003</year>). <article-title>A broken &#x003B1;-helix in folded &#x003B1;-synuclein</article-title>. <source>J. Biol. Chem.</source> <volume>278</volume>, <fpage>15313</fpage>&#x02013;<lpage>15318</lpage>. <pub-id pub-id-type="doi">10.1074/jbc.M213128200</pub-id><pub-id pub-id-type="pmid">12586824</pub-id></citation></ref>
<ref id="B45"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Chen</surname> <given-names>S. W.</given-names></name> <name><surname>Drakulic</surname> <given-names>S.</given-names></name> <name><surname>Deas</surname> <given-names>E.</given-names></name> <name><surname>Ouberai</surname> <given-names>M.</given-names></name> <name><surname>Aprile</surname> <given-names>F. A.</given-names></name> <name><surname>Arranz</surname> <given-names>R.</given-names></name> <etal/></person-group>. (<year>2015</year>). <article-title>Structural characterization of toxic oligomers that are kinetically trapped during &#x003B1;-synuclein fibril formation</article-title>. <source>Proc. Natl. Acad. Sci. U S A</source> <volume>112</volume>, <fpage>E1994</fpage>&#x02013;<lpage>E2003</lpage>. <pub-id pub-id-type="doi">10.1073/pnas.1421204112</pub-id><pub-id pub-id-type="pmid">25855634</pub-id></citation></ref>
<ref id="B46"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Chen</surname> <given-names>Y.</given-names></name> <name><surname>Yang</surname> <given-names>W.</given-names></name> <name><surname>Li</surname> <given-names>X.</given-names></name> <name><surname>Li</surname> <given-names>X.</given-names></name> <name><surname>Yang</surname> <given-names>H.</given-names></name> <name><surname>Xu</surname> <given-names>Z.</given-names></name> <etal/></person-group>. (<year>2015</year>). <article-title>&#x003B1;-Synuclein-induced internalization of NMDA receptors in hippocampal neurons is associated with reduced inward current and Ca<sup>(2+)</sup> influx upon NMDA stimulation</article-title>. <source>Neuroscience</source> <volume>300</volume>, <fpage>297</fpage>&#x02013;<lpage>306</lpage>. <pub-id pub-id-type="doi">10.1016/j.neuroscience.2015.05.035</pub-id><pub-id pub-id-type="pmid">26003734</pub-id></citation></ref>
<ref id="B47"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Cheng</surname> <given-names>H. C.</given-names></name> <name><surname>Ulane</surname> <given-names>C. M.</given-names></name> <name><surname>Burke</surname> <given-names>R. E.</given-names></name></person-group> (<year>2010</year>). <article-title>Clinical progression in Parkinson disease and the neurobiology of axons</article-title>. <source>Ann. Neurol.</source> <volume>67</volume>, <fpage>715</fpage>&#x02013;<lpage>725</lpage>. <pub-id pub-id-type="doi">10.1002/ana.21995</pub-id><pub-id pub-id-type="pmid">20517933</pub-id></citation></ref>
<ref id="B48"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Choi</surname> <given-names>I.</given-names></name> <name><surname>Zhang</surname> <given-names>Y.</given-names></name> <name><surname>Seegobin</surname> <given-names>S. P.</given-names></name> <name><surname>Pruvost</surname> <given-names>M.</given-names></name> <name><surname>Wang</surname> <given-names>Q.</given-names></name> <name><surname>Purtell</surname> <given-names>K.</given-names></name> <etal/></person-group>. (<year>2020</year>). <article-title>Microglia clear neuron-released &#x003B1;-synuclein <italic>via</italic> selective autophagy and prevent neurodegeneration</article-title>. <source>Nat. Commun.</source> <volume>11</volume>:<fpage>1386</fpage>. <pub-id pub-id-type="doi">10.1038/s41467-020-15119-w</pub-id><pub-id pub-id-type="pmid">32170061</pub-id></citation></ref>
<ref id="B49"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Chu</surname> <given-names>Y.</given-names></name> <name><surname>Muller</surname> <given-names>S.</given-names></name> <name><surname>Tavares</surname> <given-names>A.</given-names></name> <name><surname>Barret</surname> <given-names>O.</given-names></name> <name><surname>Alagille</surname> <given-names>D.</given-names></name> <name><surname>Seibyl</surname> <given-names>J.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>Intrastriatal &#x003B1;-synuclein fibrils in monkeys: spreading, imaging and neuropathological changes</article-title>. <source>Brain</source> <volume>142</volume>, <fpage>3565</fpage>&#x02013;<lpage>3579</lpage>. <pub-id pub-id-type="doi">10.1093/brain/awz296</pub-id><pub-id pub-id-type="pmid">31580415</pub-id></citation></ref>
<ref id="B50"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Clinton</surname> <given-names>L. K.</given-names></name> <name><surname>Blurton-Jones</surname> <given-names>M.</given-names></name> <name><surname>Myczek</surname> <given-names>K.</given-names></name> <name><surname>Trojanowski</surname> <given-names>J. Q.</given-names></name> <name><surname>Laferla</surname> <given-names>F. M.</given-names></name></person-group> (<year>2010</year>). <article-title>Synergistic interactions between A&#x003B2;, &#x003C4;, and &#x003B1;-synuclein: acceleration of neuropathology and cognitive decline</article-title>. <source>J. Neurosci.</source> <volume>30</volume>, <fpage>7281</fpage>&#x02013;<lpage>7289</lpage>. <pub-id pub-id-type="doi">10.1523/jneurosci.0490-10.2010</pub-id><pub-id pub-id-type="pmid">20505094</pub-id></citation></ref>
<ref id="B51"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Coon</surname> <given-names>E. A.</given-names></name> <name><surname>Cutsforth-Gregory</surname> <given-names>J. K.</given-names></name> <name><surname>Benarroch</surname> <given-names>E. E.</given-names></name></person-group> (<year>2018</year>). <article-title>Neuropathology of autonomic dysfunction in synucleinopathies</article-title>. <source>Mov. Disord.</source> <volume>33</volume>, <fpage>349</fpage>&#x02013;<lpage>358</lpage>. <pub-id pub-id-type="doi">10.1002/mds.27186</pub-id><pub-id pub-id-type="pmid">29297596</pub-id></citation></ref>
<ref id="B52"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Cremades</surname> <given-names>N.</given-names></name> <name><surname>Dobson</surname> <given-names>C. M.</given-names></name></person-group> (<year>2018</year>). <article-title>The contribution of biophysical and structural studies of protein self-assembly to the design of therapeutic strategies for amyloid diseases</article-title>. <source>Neurobiol. Dis.</source> <volume>109</volume>, <fpage>178</fpage>&#x02013;<lpage>190</lpage>. <pub-id pub-id-type="doi">10.1016/j.nbd.2017.07.009</pub-id><pub-id pub-id-type="pmid">28709995</pub-id></citation></ref>
<ref id="B53"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Croisier</surname> <given-names>E.</given-names></name> <name><surname>Moran</surname> <given-names>L. B.</given-names></name> <name><surname>Dexter</surname> <given-names>D. T.</given-names></name> <name><surname>Pearce</surname> <given-names>R. K.</given-names></name> <name><surname>Graeber</surname> <given-names>M. B.</given-names></name></person-group> (<year>2005</year>). <article-title>Microglial inflammation in the parkinsonian substantia nigra: relationship to &#x003B1;-synuclein deposition</article-title>. <source>J Neuroinflammation</source> <volume>2</volume>:<fpage>14</fpage>. <pub-id pub-id-type="doi">10.1186/1742-2094-2-14</pub-id><pub-id pub-id-type="pmid">15935098</pub-id></citation></ref>
<ref id="B54"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Danzer</surname> <given-names>K. M.</given-names></name> <name><surname>Haasen</surname> <given-names>D.</given-names></name> <name><surname>Karow</surname> <given-names>A. R.</given-names></name> <name><surname>Moussaud</surname> <given-names>S.</given-names></name> <name><surname>Habeck</surname> <given-names>M.</given-names></name> <name><surname>Giese</surname> <given-names>A.</given-names></name> <etal/></person-group>. (<year>2007</year>). <article-title>Different species of &#x003B1;-synuclein oligomers induce calcium influx and seeding</article-title>. <source>J. Neurosci.</source> <volume>27</volume>, <fpage>9220</fpage>&#x02013;<lpage>9232</lpage>. <pub-id pub-id-type="doi">10.1523/jneurosci.2617-07.2007</pub-id><pub-id pub-id-type="pmid">17715357</pub-id></citation></ref>
<ref id="B55"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Davidi</surname> <given-names>D.</given-names></name> <name><surname>Schechter</surname> <given-names>M.</given-names></name> <name><surname>Elhadi</surname> <given-names>S. A.</given-names></name> <name><surname>Matatov</surname> <given-names>A.</given-names></name> <name><surname>Nathanson</surname> <given-names>L.</given-names></name> <name><surname>Sharon</surname> <given-names>R.</given-names></name></person-group> (<year>2020</year>). <article-title>&#x003B1;-synuclein translocates to the nucleus to activate retinoic-acid-dependent gene transcription</article-title>. <source>iScience</source> <volume>23</volume>:<fpage>100910</fpage>. <pub-id pub-id-type="doi">10.2139/ssrn.3480698</pub-id><pub-id pub-id-type="pmid">32120069</pub-id></citation></ref>
<ref id="B56"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>De Oliveira</surname> <given-names>G. A. P.</given-names></name> <name><surname>Silva</surname> <given-names>J. L.</given-names></name></person-group> (<year>2019</year>). <article-title>&#x003B1;-synuclein stepwise aggregation reveals features of an early onset mutation in Parkinson&#x02019;s disease</article-title>. <source>Commun. Biol.</source> <volume>2</volume>:<fpage>374</fpage>. <pub-id pub-id-type="doi">10.1038/s42003-019-0598-9</pub-id><pub-id pub-id-type="pmid">31633065</pub-id></citation></ref>
<ref id="B57"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Decressac</surname> <given-names>M.</given-names></name> <name><surname>Kadkhodaei</surname> <given-names>B.</given-names></name> <name><surname>Mattsson</surname> <given-names>B.</given-names></name> <name><surname>Laguna</surname> <given-names>A.</given-names></name> <name><surname>Perlmann</surname> <given-names>T.</given-names></name> <name><surname>Bjorklund</surname> <given-names>A.</given-names></name></person-group> (<year>2012</year>). <article-title>&#x003B1;-Synuclein-induced down-regulation of Nurr1 disrupts GDNF signaling in nigral dopamine neurons</article-title>. <source>Sci. Transl. Med.</source> <volume>4</volume>:<fpage>163ra156</fpage>. <pub-id pub-id-type="doi">10.1126/scitranslmed.3004676</pub-id><pub-id pub-id-type="pmid">23220632</pub-id></citation></ref>
<ref id="B58"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Desplats</surname> <given-names>P.</given-names></name> <name><surname>Lee</surname> <given-names>H. J.</given-names></name> <name><surname>Bae</surname> <given-names>E. J.</given-names></name> <name><surname>Patrick</surname> <given-names>C.</given-names></name> <name><surname>Rockenstein</surname> <given-names>E.</given-names></name> <name><surname>Crews</surname> <given-names>L.</given-names></name> <etal/></person-group>. (<year>2009</year>). <article-title>Inclusion formation and neuronal cell death through neuron-to-neuron transmission of &#x003B1;-synuclein</article-title>. <source>Proc. Natl. Acad. Sci. U S A</source> <volume>106</volume>, <fpage>13010</fpage>&#x02013;<lpage>13015</lpage>. <pub-id pub-id-type="doi">10.1073/pnas.0903691106</pub-id><pub-id pub-id-type="pmid">19651612</pub-id></citation></ref>
<ref id="B59"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Devi</surname> <given-names>L.</given-names></name> <name><surname>Raghavendran</surname> <given-names>V.</given-names></name> <name><surname>Prabhu</surname> <given-names>B. M.</given-names></name> <name><surname>Avadhani</surname> <given-names>N. G.</given-names></name> <name><surname>Anandatheerthavarada</surname> <given-names>H. K.</given-names></name></person-group> (<year>2008</year>). <article-title>Mitochondrial import and accumulation of &#x003B1;-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain</article-title>. <source>J. Biol. Chem.</source> <volume>283</volume>, <fpage>9089</fpage>&#x02013;<lpage>9100</lpage>. <pub-id pub-id-type="doi">10.1074/jbc.m710012200</pub-id><pub-id pub-id-type="pmid">18245082</pub-id></citation></ref>
<ref id="B60"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Dhillon</surname> <given-names>J. S.</given-names></name> <name><surname>Trejo-Lopez</surname> <given-names>J. A.</given-names></name> <name><surname>Riffe</surname> <given-names>C.</given-names></name> <name><surname>Mcfarland</surname> <given-names>N. R.</given-names></name> <name><surname>Hiser</surname> <given-names>W. M.</given-names></name> <name><surname>Giasson</surname> <given-names>B. I.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>Dissecting &#x003B1;-synuclein inclusion pathology diversity in multiple system atrophy: implications for the prion-like transmission hypothesis</article-title>. <source>Lab. Invest.</source> <volume>99</volume>, <fpage>982</fpage>&#x02013;<lpage>992</lpage>. <pub-id pub-id-type="doi">10.1038/s41374-019-0198-9</pub-id><pub-id pub-id-type="pmid">30737468</pub-id></citation></ref>
<ref id="B62"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Dickson</surname> <given-names>D. W.</given-names></name> <name><surname>Braak</surname> <given-names>H.</given-names></name> <name><surname>Duda</surname> <given-names>J. E.</given-names></name> <name><surname>Duyckaerts</surname> <given-names>C.</given-names></name> <name><surname>Gasser</surname> <given-names>T.</given-names></name> <name><surname>Halliday</surname> <given-names>G. M.</given-names></name> <etal/></person-group>. (<year>2009</year>). <article-title>Neuropathological assessment of Parkinson&#x02019;s disease: refining the diagnostic criteria</article-title>. <source>Lancet Neurol.</source> <volume>8</volume>, <fpage>1150</fpage>&#x02013;<lpage>1157</lpage>. <pub-id pub-id-type="doi">10.1016/S1474-4422(09)70238-8</pub-id><pub-id pub-id-type="pmid">19909913</pub-id></citation></ref>
<ref id="B63"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Dijkstra</surname> <given-names>A. A.</given-names></name> <name><surname>Voorn</surname> <given-names>P.</given-names></name> <name><surname>Berendse</surname> <given-names>H. W.</given-names></name> <name><surname>Groenewegen</surname> <given-names>H. J.</given-names></name> <name><surname>Netherlands Brain</surname> <given-names>B.</given-names></name> <name><surname>Rozemuller</surname> <given-names>A. J.</given-names></name> <etal/></person-group>. (<year>2014</year>). <article-title>Stage-dependent nigral neuronal loss in incidental Lewy body and Parkinson&#x02019;s disease</article-title>. <source>Mov. Disord.</source> <volume>29</volume>, <fpage>1244</fpage>&#x02013;<lpage>1251</lpage>. <pub-id pub-id-type="doi">10.1002/mds.25952</pub-id><pub-id pub-id-type="pmid">24996051</pub-id></citation></ref>
<ref id="B61"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Di Maio</surname> <given-names>R.</given-names></name> <name><surname>Barrett</surname> <given-names>P. J.</given-names></name> <name><surname>Hoffman</surname> <given-names>E. K.</given-names></name> <name><surname>Barrett</surname> <given-names>C. W.</given-names></name> <name><surname>Zharikov</surname> <given-names>A.</given-names></name> <name><surname>Borah</surname> <given-names>A.</given-names></name> <etal/></person-group>. (<year>2016</year>). <article-title>&#x003B1;-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson&#x02019;s disease</article-title>. <source>Sci. Transl. Med.</source> <volume>8</volume>:<fpage>342ra378</fpage>. <pub-id pub-id-type="doi">10.1126/scitranslmed.aaf3634</pub-id><pub-id pub-id-type="pmid">27280685</pub-id></citation></ref>
<ref id="B64"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Don</surname> <given-names>A. S.</given-names></name> <name><surname>Hsiao</surname> <given-names>J. H.</given-names></name> <name><surname>Bleasel</surname> <given-names>J. M.</given-names></name> <name><surname>Couttas</surname> <given-names>T. A.</given-names></name> <name><surname>Halliday</surname> <given-names>G. M.</given-names></name> <name><surname>Kim</surname> <given-names>W. S.</given-names></name></person-group> (<year>2014</year>). <article-title>Altered lipid levels provide evidence for myelin dysfunction in multiple system atrophy</article-title>. <source>Acta Neuropathol. Commun.</source> <volume>2</volume>:<fpage>150</fpage>. <pub-id pub-id-type="doi">10.1186/s40478-014-0150-6</pub-id><pub-id pub-id-type="pmid">25358962</pub-id></citation></ref>
<ref id="B65"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Dong</surname> <given-names>C.</given-names></name> <name><surname>Hoffmann</surname> <given-names>M.</given-names></name> <name><surname>Li</surname> <given-names>X.</given-names></name> <name><surname>Wang</surname> <given-names>M.</given-names></name> <name><surname>Garen</surname> <given-names>C. R.</given-names></name> <name><surname>Petersen</surname> <given-names>N. O.</given-names></name> <etal/></person-group>. (<year>2018</year>). <article-title>Structural characteristics and membrane interactions of tandem &#x003B1;-synuclein oligomers</article-title>. <source>Sci. Rep.</source> <volume>8</volume>:<fpage>6755</fpage>. <pub-id pub-id-type="doi">10.1038/s41598-018-25133-0</pub-id><pub-id pub-id-type="pmid">29712958</pub-id></citation></ref>
<ref id="B66"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Doorn</surname> <given-names>K. J.</given-names></name> <name><surname>Moors</surname> <given-names>T.</given-names></name> <name><surname>Drukarch</surname> <given-names>B.</given-names></name> <name><surname>Van De Berg</surname> <given-names>W.</given-names></name> <name><surname>Lucassen</surname> <given-names>P. J.</given-names></name> <name><surname>Van Dam</surname> <given-names>A. M.</given-names></name></person-group> (<year>2014</year>). <article-title>Microglial phenotypes and toll-like receptor 2 in the substantia nigra and hippocampus of incidental Lewy body disease cases and Parkinson&#x02019;s disease patients</article-title>. <source>Acta Neuropathol. Commun.</source> <volume>2</volume>:<fpage>90</fpage>. <pub-id pub-id-type="doi">10.1186/s40478-014-0090-1</pub-id><pub-id pub-id-type="pmid">25099483</pub-id></citation></ref>
<ref id="B67"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Durante</surname> <given-names>V.</given-names></name> <name><surname>De Iure</surname> <given-names>A.</given-names></name> <name><surname>Loffredo</surname> <given-names>V.</given-names></name> <name><surname>Vaikath</surname> <given-names>N.</given-names></name> <name><surname>De Risi</surname> <given-names>M.</given-names></name> <name><surname>Paciotti</surname> <given-names>S.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>&#x003B1;-synuclein targets GluN2A NMDA receptor subunit causing striatal synaptic dysfunction and visuospatial memory alteration</article-title>. <source>Brain</source> <volume>142</volume>, <fpage>1365</fpage>&#x02013;<lpage>1385</lpage>. <pub-id pub-id-type="doi">10.1093/brain/awz065</pub-id><pub-id pub-id-type="pmid">30927362</pub-id></citation></ref>
<ref id="B68"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>El-Agnaf</surname> <given-names>O. M.</given-names></name> <name><surname>Salem</surname> <given-names>S. A.</given-names></name> <name><surname>Paleologou</surname> <given-names>K. E.</given-names></name> <name><surname>Cooper</surname> <given-names>L. J.</given-names></name> <name><surname>Fullwood</surname> <given-names>N. J.</given-names></name> <name><surname>Gibson</surname> <given-names>M. J.</given-names></name> <etal/></person-group>. (<year>2003</year>). <article-title>&#x003B1;-synuclein implicated in Parkinson&#x02019;s disease is present in extracellular biological fluids, including human plasma</article-title>. <source>FASEB J.</source> <volume>17</volume>, <fpage>1945</fpage>&#x02013;<lpage>1947</lpage>. <pub-id pub-id-type="doi">10.1096/fj.03-0098fje</pub-id><pub-id pub-id-type="pmid">14519670</pub-id></citation></ref>
<ref id="B69"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Emmanouilidou</surname> <given-names>E.</given-names></name> <name><surname>Stefanis</surname> <given-names>L.</given-names></name> <name><surname>Vekrellis</surname> <given-names>K.</given-names></name></person-group> (<year>2010</year>). <article-title>Cell-produced &#x003B1;-synuclein oligomers are targeted to and impair, the 26S proteasome</article-title>. <source>Neurobiol. Aging</source> <volume>31</volume>, <fpage>953</fpage>&#x02013;<lpage>968</lpage>. <pub-id pub-id-type="doi">10.1016/j.neurobiolaging.2008.07.008</pub-id><pub-id pub-id-type="pmid">18715677</pub-id></citation></ref>
<ref id="B70"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Engelender</surname> <given-names>S.</given-names></name> <name><surname>Isacson</surname> <given-names>O.</given-names></name></person-group> (<year>2017</year>). <article-title>The threshold theory for Parkinson&#x02019;s disease</article-title>. <source>Trends Neurosci.</source> <volume>40</volume>, <fpage>4</fpage>&#x02013;<lpage>14</lpage>. <pub-id pub-id-type="doi">10.1016/j.tins.2016.10.008</pub-id><pub-id pub-id-type="pmid">27894611</pub-id></citation></ref>
<ref id="B71"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Eschbach</surname> <given-names>J.</given-names></name> <name><surname>Von Einem</surname> <given-names>B.</given-names></name> <name><surname>M&#x000FC;ller</surname> <given-names>K.</given-names></name> <name><surname>Bayer</surname> <given-names>H.</given-names></name> <name><surname>Scheffold</surname> <given-names>A.</given-names></name> <name><surname>Morrison</surname> <given-names>B. E.</given-names></name> <etal/></person-group>. (<year>2015</year>). <article-title>Mutual exacerbation of peroxisome proliferator-activated receptor &#x003B3; coactivator 1&#x003B1; deregulation and &#x003B1;-synuclein oligomerization</article-title>. <source>Ann. Neurol.</source> <volume>77</volume>, <fpage>15</fpage>&#x02013;<lpage>32</lpage>. <pub-id pub-id-type="doi">10.1002/ana.24294</pub-id><pub-id pub-id-type="pmid">25363075</pub-id></citation></ref>
<ref id="B72"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Espay</surname> <given-names>A. J.</given-names></name> <name><surname>Kalia</surname> <given-names>L. V.</given-names></name> <name><surname>Gan-Or</surname> <given-names>Z.</given-names></name> <name><surname>Williams-Gray</surname> <given-names>C. H.</given-names></name> <name><surname>Bedard</surname> <given-names>P. L.</given-names></name> <name><surname>Rowe</surname> <given-names>S. M.</given-names></name> <etal/></person-group>. (<year>2020</year>). <article-title>Disease modification and biomarker development in Parkinson disease: revision or reconstruction?</article-title> <source>Neurology</source> <volume>94</volume>, <fpage>481</fpage>&#x02013;<lpage>494</lpage>. <pub-id pub-id-type="doi">10.1212/WNL.0000000000009107</pub-id><pub-id pub-id-type="pmid">32102975</pub-id></citation></ref>
<ref id="B73"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ettle</surname> <given-names>B.</given-names></name> <name><surname>Kerman</surname> <given-names>B. E.</given-names></name> <name><surname>Valera</surname> <given-names>E.</given-names></name> <name><surname>Gillmann</surname> <given-names>C.</given-names></name> <name><surname>Schlachetzki</surname> <given-names>J. C.</given-names></name> <name><surname>Reiprich</surname> <given-names>S.</given-names></name> <etal/></person-group>. (<year>2016</year>). <article-title>&#x003B1;-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy</article-title>. <source>Acta Neuropathol.</source> <volume>132</volume>, <fpage>59</fpage>&#x02013;<lpage>75</lpage>. <pub-id pub-id-type="doi">10.1007/s00401-016-1572-y</pub-id><pub-id pub-id-type="pmid">27059609</pub-id></citation></ref>
<ref id="B74"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ettle</surname> <given-names>B.</given-names></name> <name><surname>Reiprich</surname> <given-names>S.</given-names></name> <name><surname>Deusser</surname> <given-names>J.</given-names></name> <name><surname>Schlachetzki</surname> <given-names>J. C.</given-names></name> <name><surname>Xiang</surname> <given-names>W.</given-names></name> <name><surname>Prots</surname> <given-names>I.</given-names></name> <etal/></person-group>. (<year>2014</year>). <article-title>Intracellular &#x003B1;-synuclein affects early maturation of primary oligodendrocyte progenitor cells</article-title>. <source>Mol. Cell. Neurosci.</source> <volume>62</volume>, <fpage>68</fpage>&#x02013;<lpage>78</lpage>. <pub-id pub-id-type="doi">10.1016/j.mcn.2014.06.012</pub-id><pub-id pub-id-type="pmid">25019582</pub-id></citation></ref>
<ref id="B75"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Fanciulli</surname> <given-names>A.</given-names></name> <name><surname>Wenning</surname> <given-names>G. K.</given-names></name></person-group> (<year>2015</year>). <article-title>Multiple-system atrophy</article-title>. <source>N. Engl. J. Med.</source> <volume>372</volume>, <fpage>249</fpage>&#x02013;<lpage>263</lpage>. <pub-id pub-id-type="doi">10.1056/NEJMra1311488</pub-id><pub-id pub-id-type="pmid">25587949</pub-id></citation></ref>
<ref id="B76"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Fares</surname> <given-names>M. B.</given-names></name> <name><surname>Ait-Bouziad</surname> <given-names>N.</given-names></name> <name><surname>Dikiy</surname> <given-names>I.</given-names></name> <name><surname>Mbefo</surname> <given-names>M. K.</given-names></name> <name><surname>Jovicic</surname> <given-names>A.</given-names></name> <name><surname>Kiely</surname> <given-names>A.</given-names></name> <etal/></person-group>. (<year>2014</year>). <article-title>The novel Parkinson&#x02019;s disease linked mutation G51D attenuates <italic>in vitro</italic> aggregation and membrane binding of &#x003B1;-synuclein and enhances its secretion and nuclear localization in cells</article-title>. <source>Hum. Mol. Genet.</source> <volume>23</volume>, <fpage>4491</fpage>&#x02013;<lpage>4509</lpage>. <pub-id pub-id-type="doi">10.1093/hmg/ddu165</pub-id><pub-id pub-id-type="pmid">24728187</pub-id></citation></ref>
<ref id="B77"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Fauvet</surname> <given-names>B.</given-names></name> <name><surname>Mbefo</surname> <given-names>M. K.</given-names></name> <name><surname>Fares</surname> <given-names>M. B.</given-names></name> <name><surname>Desobry</surname> <given-names>C.</given-names></name> <name><surname>Michael</surname> <given-names>S.</given-names></name> <name><surname>Ardah</surname> <given-names>M. T.</given-names></name> <etal/></person-group>. (<year>2012</year>). <article-title>&#x003B1;-Synuclein in central nervous system and from erythrocytes, mammalian cells, and Escherichia coli exists predominantly as disordered monomer</article-title>. <source>J. Biol. Chem.</source> <volume>287</volume>, <fpage>15345</fpage>&#x02013;<lpage>15364</lpage>. <pub-id pub-id-type="doi">10.1074/jbc.M111.318949</pub-id><pub-id pub-id-type="pmid">22315227</pub-id></citation></ref>
<ref id="B78"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Fecchio</surname> <given-names>C.</given-names></name> <name><surname>Palazzi</surname> <given-names>L.</given-names></name> <name><surname>De Laureto</surname> <given-names>P. P.</given-names></name></person-group> (<year>2018</year>). <article-title>&#x003B1;-synuclein and polyunsaturated fatty acids: molecular basis of the interaction and implication in neurodegeneration</article-title>. <source>Molecules</source> <volume>23</volume>:<fpage>1531</fpage>. <pub-id pub-id-type="doi">10.3390/molecules23071531</pub-id><pub-id pub-id-type="pmid">29941855</pub-id></citation></ref>
<ref id="B79"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Fellner</surname> <given-names>L.</given-names></name> <name><surname>Irschick</surname> <given-names>R.</given-names></name> <name><surname>Schanda</surname> <given-names>K.</given-names></name> <name><surname>Reindl</surname> <given-names>M.</given-names></name> <name><surname>Klimaschewski</surname> <given-names>L.</given-names></name> <name><surname>Poewe</surname> <given-names>W.</given-names></name> <etal/></person-group>. (<year>2013</year>). <article-title>Toll-like receptor 4 is required for &#x003B1;-synuclein dependent activation of microglia and astroglia</article-title>. <source>Glia</source> <volume>61</volume>, <fpage>349</fpage>&#x02013;<lpage>360</lpage>. <pub-id pub-id-type="doi">10.1002/glia.22437</pub-id><pub-id pub-id-type="pmid">23108585</pub-id></citation></ref>
<ref id="B80"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Finkelstein</surname> <given-names>D. I.</given-names></name> <name><surname>Billings</surname> <given-names>J. L.</given-names></name> <name><surname>Adlard</surname> <given-names>P. A.</given-names></name> <name><surname>Ayton</surname> <given-names>S.</given-names></name> <name><surname>Sedjahtera</surname> <given-names>A.</given-names></name> <name><surname>Masters</surname> <given-names>C. L.</given-names></name> <etal/></person-group>. (<year>2017</year>). <article-title>The novel compound PBT434 prevents iron mediated neurodegeneration and &#x003B1;-synuclein toxicity in multiple models of Parkinson&#x02019;s disease</article-title>. <source>Acta Neuropathol. Commun.</source> <volume>5</volume>:<fpage>53</fpage>. <pub-id pub-id-type="doi">10.1186/s40478-017-0456-2</pub-id><pub-id pub-id-type="pmid">28659169</pub-id></citation></ref>
<ref id="B81"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Fitzgerald</surname> <given-names>E.</given-names></name> <name><surname>Murphy</surname> <given-names>S.</given-names></name> <name><surname>Martinson</surname> <given-names>H. A.</given-names></name></person-group> (<year>2019</year>). <article-title>&#x003B1;-synuclein pathology and the role of the microbiota in Parkinson&#x02019;s disease</article-title>. <source>Front. Neurosci.</source> <volume>13</volume>:<fpage>369</fpage>. <pub-id pub-id-type="doi">10.3389/fnins.2019.00369</pub-id><pub-id pub-id-type="pmid">31068777</pub-id></citation></ref>
<ref id="B82"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Flavin</surname> <given-names>W. P.</given-names></name> <name><surname>Bousset</surname> <given-names>L.</given-names></name> <name><surname>Green</surname> <given-names>Z. C.</given-names></name> <name><surname>Chu</surname> <given-names>Y.</given-names></name> <name><surname>Skarpathiotis</surname> <given-names>S.</given-names></name> <name><surname>Chaney</surname> <given-names>M. J.</given-names></name> <etal/></person-group>. (<year>2017</year>). <article-title>Endocytic vesicle rupture is a conserved mechanism of cellular invasion by amyloid proteins</article-title>. <source>Acta Neuropathol.</source> <volume>134</volume>, <fpage>629</fpage>&#x02013;<lpage>653</lpage>. <pub-id pub-id-type="doi">10.1007/s00401-017-1722-x</pub-id><pub-id pub-id-type="pmid">28527044</pub-id></citation></ref>
<ref id="B83"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Freundt</surname> <given-names>E. C.</given-names></name> <name><surname>Maynard</surname> <given-names>N.</given-names></name> <name><surname>Clancy</surname> <given-names>E. K.</given-names></name> <name><surname>Roy</surname> <given-names>S.</given-names></name> <name><surname>Bousset</surname> <given-names>L.</given-names></name> <name><surname>Sourigues</surname> <given-names>Y.</given-names></name> <etal/></person-group>. (<year>2012</year>). <article-title>Neuron-to-neuron transmission of &#x003B1;-synuclein fibrils through axonal transport</article-title>. <source>Ann. Neurol.</source> <volume>72</volume>, <fpage>517</fpage>&#x02013;<lpage>524</lpage>. <pub-id pub-id-type="doi">10.1002/ana.23747</pub-id><pub-id pub-id-type="pmid">23109146</pub-id></citation></ref>
<ref id="B84"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Froula</surname> <given-names>J. M.</given-names></name> <name><surname>Castellana-Cruz</surname> <given-names>M.</given-names></name> <name><surname>Anabtawi</surname> <given-names>N. M.</given-names></name> <name><surname>Camino</surname> <given-names>J. D.</given-names></name> <name><surname>Chen</surname> <given-names>S. W.</given-names></name> <name><surname>Thrasher</surname> <given-names>D. R.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>Defining &#x003B1;-synuclein species responsible for Parkinson&#x02019;s disease phenotypes in mice</article-title>. <source>J. Biol. Chem.</source> <volume>294</volume>, <fpage>10392</fpage>&#x02013;<lpage>10406</lpage>. <pub-id pub-id-type="doi">10.1074/jbc.RA119.007743</pub-id><pub-id pub-id-type="pmid">31142553</pub-id></citation></ref>
<ref id="B85"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Froula</surname> <given-names>J. M.</given-names></name> <name><surname>Henderson</surname> <given-names>B. W.</given-names></name> <name><surname>Gonzalez</surname> <given-names>J. C.</given-names></name> <name><surname>Vaden</surname> <given-names>J. H.</given-names></name> <name><surname>Mclean</surname> <given-names>J. W.</given-names></name> <name><surname>Wu</surname> <given-names>Y.</given-names></name> <etal/></person-group>. (<year>2018</year>). <article-title>&#x003B1;-Synuclein fibril-induced paradoxical structural and functional defects in hippocampal neurons</article-title>. <source>Acta Neuropathol. Commun.</source> <volume>6</volume>:<fpage>35</fpage>. <pub-id pub-id-type="doi">10.1186/s40478-018-0537-x</pub-id><pub-id pub-id-type="pmid">29716652</pub-id></citation></ref>
<ref id="B86"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Fusco</surname> <given-names>G.</given-names></name> <name><surname>Chen</surname> <given-names>S. W.</given-names></name> <name><surname>Williamson</surname> <given-names>P. T. F.</given-names></name> <name><surname>Cascella</surname> <given-names>R.</given-names></name> <name><surname>Perni</surname> <given-names>M.</given-names></name> <name><surname>Jarvis</surname> <given-names>J. A.</given-names></name> <etal/></person-group>. (<year>2017</year>). <article-title>Structural basis of membrane disruption and cellular toxicity by &#x003B1;-synuclein oligomers</article-title>. <source>Science</source> <volume>358</volume>, <fpage>1440</fpage>&#x02013;<lpage>1443</lpage>. <pub-id pub-id-type="doi">10.1126/science.aan6160</pub-id><pub-id pub-id-type="pmid">29242346</pub-id></citation></ref>
<ref id="B87"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Galvagnion</surname> <given-names>C.</given-names></name> <name><surname>Topgaard</surname> <given-names>D.</given-names></name> <name><surname>Makasewicz</surname> <given-names>K.</given-names></name> <name><surname>Buell</surname> <given-names>A. K.</given-names></name> <name><surname>Linse</surname> <given-names>S.</given-names></name> <name><surname>Sparr</surname> <given-names>E.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>Lipid dynamics and phase transition within &#x003B1;-synuclein amyloid fibrils</article-title>. <source>J. Phys. Chem. Lett.</source> <volume>10</volume>, <fpage>7872</fpage>&#x02013;<lpage>7877</lpage>. <pub-id pub-id-type="doi">10.1021/acs.jpclett.9b03005</pub-id><pub-id pub-id-type="pmid">31790267</pub-id></citation></ref>
<ref id="B88"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ganjam</surname> <given-names>G. K.</given-names></name> <name><surname>Bolte</surname> <given-names>K.</given-names></name> <name><surname>Matschke</surname> <given-names>L. A.</given-names></name> <name><surname>Neitemeier</surname> <given-names>S.</given-names></name> <name><surname>Dolga</surname> <given-names>A. M.</given-names></name> <name><surname>Hollerhage</surname> <given-names>M.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>Mitochondrial damage by &#x003B1;-synuclein causes cell death in human dopaminergic neurons</article-title>. <source>Cell Death Dis.</source> <volume>10</volume>:<fpage>865</fpage>. <pub-id pub-id-type="doi">10.1038/s41419-019-2091-2</pub-id><pub-id pub-id-type="pmid">31727879</pub-id></citation></ref>
<ref id="B89"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Gao</surname> <given-names>J.</given-names></name> <name><surname>Perera</surname> <given-names>G.</given-names></name> <name><surname>Bhadbhade</surname> <given-names>M.</given-names></name> <name><surname>Halliday</surname> <given-names>G. M.</given-names></name> <name><surname>Dzamko</surname> <given-names>N.</given-names></name></person-group> (<year>2019</year>). <article-title>Autophagy activation promotes clearance of &#x003B1;-synuclein inclusions in fibril-seeded human neural cells</article-title>. <source>J. Biol. Chem.</source> <volume>294</volume>, <fpage>14241</fpage>&#x02013;<lpage>14256</lpage>. <pub-id pub-id-type="doi">10.1074/jbc.ra119.008733</pub-id><pub-id pub-id-type="pmid">31375560</pub-id></citation></ref>
<ref id="B90"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Garretti</surname> <given-names>F.</given-names></name> <name><surname>Agalliu</surname> <given-names>D.</given-names></name> <name><surname>Lindestam Arlehamn</surname> <given-names>C. S.</given-names></name> <name><surname>Sette</surname> <given-names>A.</given-names></name> <name><surname>Sulzer</surname> <given-names>D.</given-names></name></person-group> (<year>2019</year>). <article-title>Autoimmunity in Parkinson&#x02019;s disease: the role of &#x003B1;-synuclein-specific T cells</article-title>. <source>Front. Immunol.</source> <volume>10</volume>:<fpage>303</fpage>. <pub-id pub-id-type="doi">10.3389/fimmu.2019.00303</pub-id><pub-id pub-id-type="pmid">30858851</pub-id></citation></ref>
<ref id="B91"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Gerhard</surname> <given-names>A.</given-names></name> <name><surname>Banati</surname> <given-names>R. B.</given-names></name> <name><surname>Goerres</surname> <given-names>G. B.</given-names></name> <name><surname>Cagnin</surname> <given-names>A.</given-names></name> <name><surname>Myers</surname> <given-names>R.</given-names></name> <name><surname>Gunn</surname> <given-names>R. N.</given-names></name> <etal/></person-group>. (<year>2003</year>). <article-title>[<sup>11</sup>C](R)-PK11195 PET imaging of microglial activation in multiple system atrophy</article-title>. <source>Neurology</source> <volume>61</volume>, <fpage>686</fpage>&#x02013;<lpage>689</lpage>. <pub-id pub-id-type="doi">10.1212/01.wnl.0000078192.95645.e6</pub-id><pub-id pub-id-type="pmid">12963764</pub-id></citation></ref>
<ref id="B92"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Gerhard</surname> <given-names>A.</given-names></name> <name><surname>Pavese</surname> <given-names>N.</given-names></name> <name><surname>Hotton</surname> <given-names>G.</given-names></name> <name><surname>Turkheimer</surname> <given-names>F.</given-names></name> <name><surname>Es</surname> <given-names>M.</given-names></name> <name><surname>Hammers</surname> <given-names>A.</given-names></name> <etal/></person-group>. (<year>2006</year>). <article-title><italic>In vivo</italic> imaging of microglial activation with [<sup>11</sup>C](R)-PK11195 PET in idiopathic Parkinson&#x02019;s disease</article-title>. <source>Neurobiol. Dis.</source> <volume>21</volume>, <fpage>404</fpage>&#x02013;<lpage>412</lpage>. <pub-id pub-id-type="doi">10.1016/j.nbd.2005.08.002</pub-id><pub-id pub-id-type="pmid">16182554</pub-id></citation></ref>
<ref id="B93"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ghiglieri</surname> <given-names>V.</given-names></name> <name><surname>Calabrese</surname> <given-names>V.</given-names></name> <name><surname>Calabresi</surname> <given-names>P.</given-names></name></person-group> (<year>2018</year>). <article-title>&#x003B1;-synuclein: from early synaptic dysfunction to neurodegeneration</article-title>. <source>Front. Neurol.</source> <volume>9</volume>:<fpage>295</fpage>. <pub-id pub-id-type="doi">10.3389/fneur.2018.00295</pub-id><pub-id pub-id-type="pmid">29780350</pub-id></citation></ref>
<ref id="B94"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ghosh</surname> <given-names>D.</given-names></name> <name><surname>Sahay</surname> <given-names>S.</given-names></name> <name><surname>Ranjan</surname> <given-names>P.</given-names></name> <name><surname>Salot</surname> <given-names>S.</given-names></name> <name><surname>Mohite</surname> <given-names>G. M.</given-names></name> <name><surname>Singh</surname> <given-names>P. K.</given-names></name> <etal/></person-group>. (<year>2014</year>). <article-title>The newly discovered Parkinson&#x02019;s disease associated Finnish mutation (A53E) attenuates &#x003B1;-synuclein aggregation and membrane binding</article-title>. <source>Biochemistry</source> <volume>53</volume>, <fpage>6419</fpage>&#x02013;<lpage>6421</lpage>. <pub-id pub-id-type="doi">10.1021/bi5010365</pub-id><pub-id pub-id-type="pmid">25268550</pub-id></citation></ref>
<ref id="B95"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Giasson</surname> <given-names>B. I.</given-names></name> <name><surname>Duda</surname> <given-names>J. E.</given-names></name> <name><surname>Murray</surname> <given-names>I. V.</given-names></name> <name><surname>Chen</surname> <given-names>Q.</given-names></name> <name><surname>Souza</surname> <given-names>J. M.</given-names></name> <name><surname>Hurtig</surname> <given-names>H. I.</given-names></name> <etal/></person-group>. (<year>2000</year>). <article-title>Oxidative damage linked to neurodegeneration by selective &#x003B1;-synuclein nitration in synucleinopathy lesions</article-title>. <source>Science</source> <volume>290</volume>, <fpage>985</fpage>&#x02013;<lpage>989</lpage>. <pub-id pub-id-type="doi">10.1126/science.290.5493.985</pub-id><pub-id pub-id-type="pmid">11062131</pub-id></citation></ref>
<ref id="B96"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Giordano</surname> <given-names>N.</given-names></name> <name><surname>Iemolo</surname> <given-names>A.</given-names></name> <name><surname>Mancini</surname> <given-names>M.</given-names></name> <name><surname>Cacace</surname> <given-names>F.</given-names></name> <name><surname>De Risi</surname> <given-names>M.</given-names></name> <name><surname>Latagliata</surname> <given-names>E. C.</given-names></name> <etal/></person-group>. (<year>2018</year>). <article-title>Motor learning and metaplasticity in striatal neurons: relevance for Parkinson&#x02019;s disease</article-title>. <source>Brain</source> <volume>141</volume>, <fpage>505</fpage>&#x02013;<lpage>520</lpage>. <pub-id pub-id-type="doi">10.1093/brain/awx351</pub-id><pub-id pub-id-type="pmid">29281030</pub-id></citation></ref>
<ref id="B97"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Goedert</surname> <given-names>M.</given-names></name> <name><surname>Spillantini</surname> <given-names>M. G.</given-names></name></person-group> (<year>1998</year>). <article-title>Lewy body diseases and multiple system atrophy as alpha-synucleinopathies</article-title>. <source>Mol. Psychiatry</source> <volume>3</volume>, <fpage>462</fpage>&#x02013;<lpage>465</lpage>. <pub-id pub-id-type="doi">10.1038/sj.mp.4000458</pub-id><pub-id pub-id-type="pmid">9857966</pub-id></citation></ref>
<ref id="B98"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Gonzalez</surname> <given-names>N.</given-names></name> <name><surname>Arcos-Lopez</surname> <given-names>T.</given-names></name> <name><surname>Konig</surname> <given-names>A.</given-names></name> <name><surname>Quintanar</surname> <given-names>L.</given-names></name> <name><surname>Menacho Marquez</surname> <given-names>M.</given-names></name> <name><surname>Outeiro</surname> <given-names>T. F.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>Effects of &#x003B1;-synuclein post-translational modifications on metal binding</article-title>. <source>J. Neurochem.</source> <volume>150</volume>, <fpage>507</fpage>&#x02013;<lpage>521</lpage>. <pub-id pub-id-type="doi">10.1111/jnc.14721</pub-id><pub-id pub-id-type="pmid">31099098</pub-id></citation></ref>
<ref id="B99"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Gosavi</surname> <given-names>N.</given-names></name> <name><surname>Lee</surname> <given-names>H. J.</given-names></name> <name><surname>Lee</surname> <given-names>J. S.</given-names></name> <name><surname>Patel</surname> <given-names>S.</given-names></name> <name><surname>Lee</surname> <given-names>S. J.</given-names></name></person-group> (<year>2002</year>). <article-title>Golgi fragmentation occurs in the cells with prefibrillar &#x003B1;-synuclein aggregates and precedes the formation of fibrillar inclusion</article-title>. <source>J. Biol. Chem.</source> <volume>277</volume>, <fpage>48984</fpage>&#x02013;<lpage>48992</lpage>. <pub-id pub-id-type="doi">10.1074/jbc.m208194200</pub-id><pub-id pub-id-type="pmid">12351643</pub-id></citation></ref>
<ref id="B100"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Grey</surname> <given-names>M.</given-names></name> <name><surname>Linse</surname> <given-names>S.</given-names></name> <name><surname>Nilsson</surname> <given-names>H.</given-names></name> <name><surname>Brundin</surname> <given-names>P.</given-names></name> <name><surname>Sparr</surname> <given-names>E.</given-names></name></person-group> (<year>2011</year>). <article-title>Membrane interaction of &#x003B1;-synuclein in different aggregation states</article-title>. <source>J. Parkinsons Dis.</source> <volume>1</volume>, <fpage>359</fpage>&#x02013;<lpage>371</lpage>. <pub-id pub-id-type="doi">10.3233/JPD-2011-11067</pub-id><pub-id pub-id-type="pmid">23933657</pub-id></citation></ref>
<ref id="B101"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Guardia-Laguarta</surname> <given-names>C.</given-names></name> <name><surname>Area-Gomez</surname> <given-names>E.</given-names></name> <name><surname>Rub</surname> <given-names>C.</given-names></name> <name><surname>Liu</surname> <given-names>Y.</given-names></name> <name><surname>Magrane</surname> <given-names>J.</given-names></name> <name><surname>Becker</surname> <given-names>D.</given-names></name> <etal/></person-group>. (<year>2014</year>). <article-title>&#x003B1;-Synuclein is localized to mitochondria-associated ER membranes</article-title>. <source>J. Neurosci.</source> <volume>34</volume>, <fpage>249</fpage>&#x02013;<lpage>259</lpage>. <pub-id pub-id-type="doi">10.1523/JNEUROSCI.2507-13.2014</pub-id><pub-id pub-id-type="pmid">24381286</pub-id></citation></ref>
<ref id="B102"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Guerrero-Ferreira</surname> <given-names>R.</given-names></name> <name><surname>Taylor</surname> <given-names>N. M.</given-names></name> <name><surname>Arteni</surname> <given-names>A. A.</given-names></name> <name><surname>Kumari</surname> <given-names>P.</given-names></name> <name><surname>Mona</surname> <given-names>D.</given-names></name> <name><surname>Ringler</surname> <given-names>P.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>Two new polymorphic structures of human full-length &#x003B1;-synuclein fibrils solved by cryo-electron microscopy</article-title>. <source>eLife</source> <volume>8</volume>:<fpage>e48907</fpage>. <pub-id pub-id-type="doi">10.7554/eLife.48907</pub-id><pub-id pub-id-type="pmid">31815671</pub-id></citation></ref>
<ref id="B103"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Guo</surname> <given-names>J. L.</given-names></name> <name><surname>Covell</surname> <given-names>D. J.</given-names></name> <name><surname>Daniels</surname> <given-names>J. P.</given-names></name> <name><surname>Iba</surname> <given-names>M.</given-names></name> <name><surname>Stieber</surname> <given-names>A.</given-names></name> <name><surname>Zhang</surname> <given-names>B.</given-names></name> <etal/></person-group>. (<year>2013</year>). <article-title>Distinct &#x003B1;-synuclein strains differentially promote tau inclusions in neurons</article-title>. <source>Cell</source> <volume>154</volume>, <fpage>103</fpage>&#x02013;<lpage>117</lpage>. <pub-id pub-id-type="doi">10.1016/j.cell.2013.05.057</pub-id><pub-id pub-id-type="pmid">23827677</pub-id></citation></ref>
<ref id="B104"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Hallett</surname> <given-names>P. J.</given-names></name> <name><surname>Cooper</surname> <given-names>O.</given-names></name> <name><surname>Sadi</surname> <given-names>D.</given-names></name> <name><surname>Robertson</surname> <given-names>H.</given-names></name> <name><surname>Mendez</surname> <given-names>I.</given-names></name> <name><surname>Isacson</surname> <given-names>O.</given-names></name></person-group> (<year>2014</year>). <article-title>Long-term health of dopaminergic neuron transplants in Parkinson&#x02019;s disease patients</article-title>. <source>Cell Rep.</source> <volume>7</volume>, <fpage>1755</fpage>&#x02013;<lpage>1761</lpage>. <pub-id pub-id-type="doi">10.1016/j.celrep.2014.05.027</pub-id><pub-id pub-id-type="pmid">24910427</pub-id></citation></ref>
<ref id="B105"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Halliday</surname> <given-names>G.</given-names></name> <name><surname>Mccann</surname> <given-names>H.</given-names></name> <name><surname>Shepherd</surname> <given-names>C.</given-names></name></person-group> (<year>2012</year>). <article-title>Evaluation of the Braak hypothesis: how far can it explain the pathogenesis of Parkinson&#x02019;s disease?</article-title> <source>Expert Rev. Neurother.</source> <volume>12</volume>, <fpage>673</fpage>&#x02013;<lpage>686</lpage>. <pub-id pub-id-type="doi">10.1586/ern.12.47</pub-id><pub-id pub-id-type="pmid">22650170</pub-id></citation></ref>
<ref id="B106"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Halliday</surname> <given-names>G. M.</given-names></name> <name><surname>Stevens</surname> <given-names>C. H.</given-names></name></person-group> (<year>2011</year>). <article-title>Glia: initiators and progressors of pathology in Parkinson&#x02019;s disease</article-title>. <source>Mov. Disord.</source> <volume>26</volume>, <fpage>6</fpage>&#x02013;<lpage>17</lpage>. <pub-id pub-id-type="doi">10.1002/mds.23455</pub-id><pub-id pub-id-type="pmid">21322014</pub-id></citation></ref>
<ref id="B107"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Hegde</surname> <given-names>M. L.</given-names></name> <name><surname>Rao</surname> <given-names>K. S.</given-names></name></person-group> (<year>2007</year>). <article-title>DNA induces folding in &#x003B1;-synuclein: understanding the mechanism using chaperone property of osmolytes</article-title>. <source>Arch. Biochem. Biophys.</source> <volume>464</volume>, <fpage>57</fpage>&#x02013;<lpage>69</lpage>. <pub-id pub-id-type="doi">10.1016/j.abb.2007.03.042</pub-id><pub-id pub-id-type="pmid">17537399</pub-id></citation></ref>
<ref id="B108"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Heras-Garvin</surname> <given-names>A.</given-names></name> <name><surname>Stefanova</surname> <given-names>N.</given-names></name></person-group> (<year>2020</year>). <article-title>MSA: from basic mechanisms to experimental therapeutics</article-title>. <source>Parkinsonism Relat. Disord.</source> <volume>73</volume>, <fpage>94</fpage>&#x02013;<lpage>104</lpage>. <pub-id pub-id-type="doi">10.1016/j.parkreldis.2020.01.010</pub-id><pub-id pub-id-type="pmid">32005598</pub-id></citation></ref>
<ref id="B109"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Heras-Garvin</surname> <given-names>A.</given-names></name> <name><surname>Weckbecker</surname> <given-names>D.</given-names></name> <name><surname>Ryazanov</surname> <given-names>S.</given-names></name> <name><surname>Leonov</surname> <given-names>A.</given-names></name> <name><surname>Griesinger</surname> <given-names>C.</given-names></name> <name><surname>Giese</surname> <given-names>A.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>Anle138b modulates &#x003B1;-synuclein oligomerization and prevents motor decline and neurodegeneration in a mouse model of multiple system atrophy</article-title>. <source>Mov. Disord.</source> <volume>34</volume>, <fpage>255</fpage>&#x02013;<lpage>263</lpage>. <pub-id pub-id-type="doi">10.1002/mds.27562</pub-id><pub-id pub-id-type="pmid">30452793</pub-id></citation></ref>
<ref id="B110"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Hijaz</surname> <given-names>B. A.</given-names></name> <name><surname>Volpicelli-Daley</surname> <given-names>L. A.</given-names></name></person-group> (<year>2020</year>). <article-title>Initiation and propagation of &#x003B1;-synuclein aggregation in the nervous system</article-title>. <source>Mol. Neurodegener.</source> <volume>15</volume>:<fpage>19</fpage>. <pub-id pub-id-type="doi">10.1186/s13024-020-00368-6</pub-id><pub-id pub-id-type="pmid">32143659</pub-id></citation></ref>
<ref id="B111"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Hoffmann</surname> <given-names>A.</given-names></name> <name><surname>Ettle</surname> <given-names>B.</given-names></name> <name><surname>Battis</surname> <given-names>K.</given-names></name> <name><surname>Reiprich</surname> <given-names>S.</given-names></name> <name><surname>Schlachetzki</surname> <given-names>J. C. M.</given-names></name> <name><surname>Masliah</surname> <given-names>E.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>Oligodendroglial &#x003B1;-synucleinopathy-driven neuroinflammation in multiple system atrophy</article-title>. <source>Brain Pathol.</source> <volume>29</volume>, <fpage>380</fpage>&#x02013;<lpage>396</lpage>. <pub-id pub-id-type="doi">10.1111/bpa.12678</pub-id><pub-id pub-id-type="pmid">30444295</pub-id></citation></ref>
<ref id="B112"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Holmes</surname> <given-names>B. B.</given-names></name> <name><surname>Devos</surname> <given-names>S. L.</given-names></name> <name><surname>Kfoury</surname> <given-names>N.</given-names></name> <name><surname>Li</surname> <given-names>M.</given-names></name> <name><surname>Jacks</surname> <given-names>R.</given-names></name> <name><surname>Yanamandra</surname> <given-names>K.</given-names></name> <etal/></person-group>. (<year>2013</year>). <article-title>Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds</article-title>. <source>Proc. Natl. Acad. Sci. U S A</source> <volume>110</volume>, <fpage>E3138</fpage>&#x02013;<lpage>E3147</lpage>. <pub-id pub-id-type="doi">10.1073/pnas.1301440110</pub-id><pub-id pub-id-type="pmid">23898162</pub-id></citation></ref>
<ref id="B113"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Holmqvist</surname> <given-names>S.</given-names></name> <name><surname>Chutna</surname> <given-names>O.</given-names></name> <name><surname>Bousset</surname> <given-names>L.</given-names></name> <name><surname>Aldrin-Kirk</surname> <given-names>P.</given-names></name> <name><surname>Li</surname> <given-names>W.</given-names></name> <name><surname>Bjorklund</surname> <given-names>T.</given-names></name> <etal/></person-group>. (<year>2014</year>). <article-title>Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats</article-title>. <source>Acta Neuropathol.</source> <volume>128</volume>, <fpage>805</fpage>&#x02013;<lpage>820</lpage>. <pub-id pub-id-type="doi">10.1007/s00401-014-1343-6</pub-id><pub-id pub-id-type="pmid">25296989</pub-id></citation></ref>
<ref id="B114"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Hoozemans</surname> <given-names>J. J.</given-names></name> <name><surname>Van Haastert</surname> <given-names>E. S.</given-names></name> <name><surname>Eikelenboom</surname> <given-names>P.</given-names></name> <name><surname>De Vos</surname> <given-names>R. A.</given-names></name> <name><surname>Rozemuller</surname> <given-names>J. M.</given-names></name> <name><surname>Scheper</surname> <given-names>W.</given-names></name></person-group> (<year>2007</year>). <article-title>Activation of the unfolded protein response in Parkinson&#x02019;s disease</article-title>. <source>Biochem. Biophys. Res. Commun.</source> <volume>354</volume>, <fpage>707</fpage>&#x02013;<lpage>711</lpage>. <pub-id pub-id-type="doi">10.1016/j.bbrc.2007.01.043</pub-id><pub-id pub-id-type="pmid">17254549</pub-id></citation></ref>
<ref id="B115"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Hsu</surname> <given-names>L. J.</given-names></name> <name><surname>Sagara</surname> <given-names>Y.</given-names></name> <name><surname>Arroyo</surname> <given-names>A.</given-names></name> <name><surname>Rockenstein</surname> <given-names>E.</given-names></name> <name><surname>Sisk</surname> <given-names>A.</given-names></name> <name><surname>Mallory</surname> <given-names>M.</given-names></name> <etal/></person-group>. (<year>2000</year>). <article-title>&#x003B1;-synuclein promotes mitochondrial deficit and oxidative stress</article-title>. <source>Am. J. Pathol.</source> <volume>157</volume>, <fpage>401</fpage>&#x02013;<lpage>410</lpage>. <pub-id pub-id-type="doi">10.1016/s0002-9440(10)64553-1</pub-id><pub-id pub-id-type="pmid">10934145</pub-id></citation></ref>
<ref id="B116"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Iljina</surname> <given-names>M.</given-names></name> <name><surname>Garcia</surname> <given-names>G. A.</given-names></name> <name><surname>Horrocks</surname> <given-names>M. H.</given-names></name> <name><surname>Tosatto</surname> <given-names>L.</given-names></name> <name><surname>Choi</surname> <given-names>M. L.</given-names></name> <name><surname>Ganzinger</surname> <given-names>K. A.</given-names></name> <etal/></person-group>. (<year>2016</year>). <article-title>Kinetic model of the aggregation of &#x003B1;-synuclein provides insights into prion-like spreading</article-title>. <source>Proc. Natl. Acad. Sci. U S A</source> <volume>113</volume>, <fpage>E1206</fpage>&#x02013;<lpage>E1215</lpage>. <pub-id pub-id-type="doi">10.1073/pnas.1524128113</pub-id><pub-id pub-id-type="pmid">26884195</pub-id></citation></ref>
<ref id="B117"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Imamura</surname> <given-names>K.</given-names></name> <name><surname>Hishikawa</surname> <given-names>N.</given-names></name> <name><surname>Sawada</surname> <given-names>M.</given-names></name> <name><surname>Nagatsu</surname> <given-names>T.</given-names></name> <name><surname>Yoshida</surname> <given-names>M.</given-names></name> <name><surname>Hashizume</surname> <given-names>Y.</given-names></name></person-group> (<year>2003</year>). <article-title>Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson&#x02019;s disease brains</article-title>. <source>Acta Neuropathol.</source> <volume>106</volume>, <fpage>518</fpage>&#x02013;<lpage>526</lpage>. <pub-id pub-id-type="doi">10.1007/s00401-003-0766-2</pub-id><pub-id pub-id-type="pmid">14513261</pub-id></citation></ref>
<ref id="B118"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Iranzo</surname> <given-names>A.</given-names></name> <name><surname>Tolosa</surname> <given-names>E.</given-names></name> <name><surname>Gelpi</surname> <given-names>E.</given-names></name> <name><surname>Molinuevo</surname> <given-names>J. L.</given-names></name> <name><surname>Valldeoriola</surname> <given-names>F.</given-names></name> <name><surname>Serradell</surname> <given-names>M.</given-names></name> <etal/></person-group>. (<year>2013</year>). <article-title>Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder: an observational cohort study</article-title>. <source>Lancet Neurol.</source> <volume>12</volume>, <fpage>443</fpage>&#x02013;<lpage>453</lpage>. <pub-id pub-id-type="doi">10.1016/S1474-4422(13)70056-5</pub-id><pub-id pub-id-type="pmid">23562390</pub-id></citation></ref>
<ref id="B119"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Irwin</surname> <given-names>D. J.</given-names></name> <name><surname>Abrams</surname> <given-names>J. Y.</given-names></name> <name><surname>Schonberger</surname> <given-names>L. B.</given-names></name> <name><surname>Leschek</surname> <given-names>E. W.</given-names></name> <name><surname>Mills</surname> <given-names>J. L.</given-names></name> <name><surname>Lee</surname> <given-names>V. M.</given-names></name> <etal/></person-group>. (<year>2013</year>). <article-title>Evaluation of potential infectivity of Alzheimer and Parkinson disease proteins in recipients of cadaver-derived human growth hormone</article-title>. <source>JAMA Neurol.</source> <volume>70</volume>, <fpage>462</fpage>&#x02013;<lpage>468</lpage>. <pub-id pub-id-type="doi">10.1001/jamaneurol.2013.1933</pub-id><pub-id pub-id-type="pmid">23380910</pub-id></citation></ref>
<ref id="B120"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ishizawa</surname> <given-names>K.</given-names></name> <name><surname>Komori</surname> <given-names>T.</given-names></name> <name><surname>Arai</surname> <given-names>N.</given-names></name> <name><surname>Mizutani</surname> <given-names>T.</given-names></name> <name><surname>Hirose</surname> <given-names>T.</given-names></name></person-group> (<year>2008</year>). <article-title>Glial cytoplasmic inclusions and tissue injury in multiple system atrophy: A quantitative study in white matter (olivopontocerebellar system) and gray matter (nigrostriatal system)</article-title>. <source>Neuropathology</source> <volume>28</volume>, <fpage>249</fpage>&#x02013;<lpage>257</lpage>. <pub-id pub-id-type="doi">10.1111/j.1440-1789.2007.00855.x</pub-id><pub-id pub-id-type="pmid">18312549</pub-id></citation></ref>
<ref id="B121"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ishizawa</surname> <given-names>K.</given-names></name> <name><surname>Komori</surname> <given-names>T.</given-names></name> <name><surname>Sasaki</surname> <given-names>S.</given-names></name> <name><surname>Arai</surname> <given-names>N.</given-names></name> <name><surname>Mizutani</surname> <given-names>T.</given-names></name> <name><surname>Hirose</surname> <given-names>T.</given-names></name></person-group> (<year>2004</year>). <article-title>Microglial activation parallels system degeneration in multiple system atrophy</article-title>. <source>J. Neuropathol. Exp. Neurol.</source> <volume>63</volume>, <fpage>43</fpage>&#x02013;<lpage>52</lpage>. <pub-id pub-id-type="doi">10.1093/jnen/63.1.43</pub-id><pub-id pub-id-type="pmid">14748560</pub-id></citation></ref>
<ref id="B122"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Jellinger</surname> <given-names>K. A.</given-names></name></person-group> (<year>2009</year>). <article-title>A critical evaluation of current staging of &#x003B1;-synuclein pathology in Lewy body disorders</article-title>. <source>Biochim. Biophys. Acta</source> <volume>1792</volume>, <fpage>730</fpage>&#x02013;<lpage>740</lpage>. <pub-id pub-id-type="doi">10.1016/j.bbadis.2008.07.006</pub-id><pub-id pub-id-type="pmid">18718530</pub-id></citation></ref>
<ref id="B123"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Jellinger</surname> <given-names>K. A.</given-names></name></person-group> (<year>2018</year>). <article-title>Dementia with Lewy bodies and Parkinson&#x02019;s disease-dementia: current concepts and controversies</article-title>. <source>J. Neural Transm.</source> <volume>125</volume>, <fpage>615</fpage>&#x02013;<lpage>650</lpage>. <pub-id pub-id-type="doi">10.1007/s00702-017-1821-9</pub-id><pub-id pub-id-type="pmid">29222591</pub-id></citation></ref>
<ref id="B124"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kaji</surname> <given-names>S.</given-names></name> <name><surname>Maki</surname> <given-names>T.</given-names></name> <name><surname>Ishimoto</surname> <given-names>T.</given-names></name> <name><surname>Yamakado</surname> <given-names>H.</given-names></name> <name><surname>Takahashi</surname> <given-names>R.</given-names></name></person-group> (<year>2020</year>). <article-title>Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions</article-title>. <source>Transl. Neurodegener.</source> <volume>9</volume>:<fpage>7</fpage>. <pub-id pub-id-type="doi">10.1186/s40035-020-0185-5</pub-id><pub-id pub-id-type="pmid">32095235</pub-id></citation></ref>
<ref id="B125"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kaji</surname> <given-names>S.</given-names></name> <name><surname>Maki</surname> <given-names>T.</given-names></name> <name><surname>Kinoshita</surname> <given-names>H.</given-names></name> <name><surname>Uemura</surname> <given-names>N.</given-names></name> <name><surname>Ayaki</surname> <given-names>T.</given-names></name> <name><surname>Kawamoto</surname> <given-names>Y.</given-names></name> <etal/></person-group>. (<year>2018</year>). <article-title>Pathological endogenous &#x003B1;-synuclein accumulation in oligodendrocyte precursor cells potentially induces inclusions in multiple system atrophy</article-title>. <source>Stem Cell Reports</source> <volume>10</volume>, <fpage>356</fpage>&#x02013;<lpage>365</lpage>. <pub-id pub-id-type="doi">10.1016/j.stemcr.2017.12.001</pub-id><pub-id pub-id-type="pmid">29337114</pub-id></citation></ref>
<ref id="B126"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kalaitzakis</surname> <given-names>M. E.</given-names></name> <name><surname>Graeber</surname> <given-names>M. B.</given-names></name> <name><surname>Gentleman</surname> <given-names>S. M.</given-names></name> <name><surname>Pearce</surname> <given-names>R. K.</given-names></name></person-group> (<year>2008</year>). <article-title>The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson&#x02019;s disease: a critical analysis of &#x003B1;-synuclein staging</article-title>. <source>Neuropathol. Appl. Neurobiol.</source> <volume>34</volume>, <fpage>284</fpage>&#x02013;<lpage>295</lpage>. <pub-id pub-id-type="doi">10.1111/j.1365-2990.2007.00923.x</pub-id></citation></ref>
<ref id="B127"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kalia</surname> <given-names>L. V.</given-names></name> <name><surname>Lang</surname> <given-names>A. E.</given-names></name></person-group> (<year>2015</year>). <article-title>Parkinson&#x02019;s disease</article-title>. <source>Lancet</source> <volume>386</volume>, <fpage>896</fpage>&#x02013;<lpage>912</lpage>. <pub-id pub-id-type="doi">10.1016/S0140-6736(14)61393-3</pub-id><pub-id pub-id-type="pmid">25904081</pub-id></citation></ref>
<ref id="B128"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kam</surname> <given-names>T. I.</given-names></name> <name><surname>Mao</surname> <given-names>X.</given-names></name> <name><surname>Park</surname> <given-names>H.</given-names></name> <name><surname>Chou</surname> <given-names>S. C.</given-names></name> <name><surname>Karuppagounder</surname> <given-names>S. S.</given-names></name> <name><surname>Umanah</surname> <given-names>G. E.</given-names></name> <etal/></person-group>. (<year>2018</year>). <article-title>Poly(ADP-ribose) drives pathologic &#x003B1;-synuclein neurodegeneration in Parkinson&#x02019;s disease</article-title>. <source>Science</source> <volume>362</volume>:<fpage>eaat8407</fpage>. <pub-id pub-id-type="doi">10.1126/science.aat8407</pub-id><pub-id pub-id-type="pmid">30385548</pub-id></citation></ref>
<ref id="B129"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kara</surname> <given-names>E.</given-names></name> <name><surname>Marks</surname> <given-names>J. D.</given-names></name> <name><surname>Aguzzi</surname> <given-names>A.</given-names></name></person-group> (<year>2018</year>). <article-title>Toxic protein spread in neurodegeneration: reality versus fantasy</article-title>. <source>Trends Mol. Med.</source> <volume>24</volume>, <fpage>1007</fpage>&#x02013;<lpage>1020</lpage>. <pub-id pub-id-type="doi">10.1016/j.molmed.2018.09.004</pub-id><pub-id pub-id-type="pmid">30442495</pub-id></citation></ref>
<ref id="B130"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Katorcha</surname> <given-names>E.</given-names></name> <name><surname>Makarava</surname> <given-names>N.</given-names></name> <name><surname>Lee</surname> <given-names>Y. J.</given-names></name> <name><surname>Lindberg</surname> <given-names>I.</given-names></name> <name><surname>Monteiro</surname> <given-names>M. J.</given-names></name> <name><surname>Kovacs</surname> <given-names>G. G.</given-names></name> <etal/></person-group>. (<year>2017</year>). <article-title>Cross-seeding of prions by aggregated &#x003B1;-synuclein leads to transmissible spongiform encephalopathy</article-title>. <source>PLoS Pathog.</source> <volume>13</volume>:<fpage>e1006563</fpage>. <pub-id pub-id-type="doi">10.1371/journal.ppat.1006563</pub-id><pub-id pub-id-type="pmid">28797122</pub-id></citation></ref>
<ref id="B131"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kaufmann</surname> <given-names>H.</given-names></name> <name><surname>Hague</surname> <given-names>K.</given-names></name> <name><surname>Perl</surname> <given-names>D.</given-names></name></person-group> (<year>2001</year>). <article-title>Accumulation of &#x003B1;-synuclein in autonomic nerves in pure autonomic failure</article-title>. <source>Neurology</source> <volume>56</volume>, <fpage>980</fpage>&#x02013;<lpage>981</lpage>. <pub-id pub-id-type="doi">10.1212/wnl.56.7.980</pub-id><pub-id pub-id-type="pmid">11294945</pub-id></citation></ref>
<ref id="B132"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kaufmann</surname> <given-names>H.</given-names></name> <name><surname>Nahm</surname> <given-names>K.</given-names></name> <name><surname>Purohit</surname> <given-names>D.</given-names></name> <name><surname>Wolfe</surname> <given-names>D.</given-names></name></person-group> (<year>2004</year>). <article-title>Autonomic failure as the initial presentation of Parkinson disease and dementia with Lewy bodies</article-title>. <source>Neurology</source> <volume>63</volume>, <fpage>1093</fpage>&#x02013;<lpage>1095</lpage>. <pub-id pub-id-type="doi">10.1212/01.wnl.0000138500.73671.dc</pub-id><pub-id pub-id-type="pmid">15452307</pub-id></citation></ref>
<ref id="B133"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kim</surname> <given-names>C.</given-names></name> <name><surname>Ho</surname> <given-names>D. H.</given-names></name> <name><surname>Suk</surname> <given-names>J. E.</given-names></name> <name><surname>You</surname> <given-names>S.</given-names></name> <name><surname>Michael</surname> <given-names>S.</given-names></name> <name><surname>Kang</surname> <given-names>J.</given-names></name> <etal/></person-group>. (<year>2013</year>). <article-title>Neuron-released oligomeric &#x003B1;-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia</article-title>. <source>Nat. Commun.</source> <volume>4</volume>:<fpage>1562</fpage>. <pub-id pub-id-type="doi">10.1038/ncomms2534</pub-id><pub-id pub-id-type="pmid">23463005</pub-id></citation></ref>
<ref id="B134"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kim</surname> <given-names>J. Y.</given-names></name> <name><surname>Illigens</surname> <given-names>B. M.</given-names></name> <name><surname>Mccormick</surname> <given-names>M. P.</given-names></name> <name><surname>Wang</surname> <given-names>N.</given-names></name> <name><surname>Gibbons</surname> <given-names>C. H.</given-names></name></person-group> (<year>2019</year>). <article-title>&#x003B1;-synuclein in skin nerve fibers as a biomarker for &#x003B1;-synucleinopathies</article-title>. <source>J. Clin. Neurol.</source> <volume>15</volume>, <fpage>135</fpage>&#x02013;<lpage>142</lpage>. <pub-id pub-id-type="doi">10.3988/jcn.2019.15.2.135</pub-id><pub-id pub-id-type="pmid">30938106</pub-id></citation></ref>
<ref id="B135"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kim</surname> <given-names>S.</given-names></name> <name><surname>Kwon</surname> <given-names>S. H.</given-names></name> <name><surname>Kam</surname> <given-names>T. I.</given-names></name> <name><surname>Panicker</surname> <given-names>N.</given-names></name> <name><surname>Karuppagounder</surname> <given-names>S. S.</given-names></name> <name><surname>Lee</surname> <given-names>S.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>Transneuronal propagation of pathologic &#x003B1;-synuclein from the gut to the brain models Parkinson&#x02019;s disease</article-title>. <source>Neuron</source> <volume>103</volume>, <fpage>627.e7</fpage>&#x02013;<lpage>641.e7</lpage>. <pub-id pub-id-type="doi">10.1016/j.neuron.2019.05.035</pub-id><pub-id pub-id-type="pmid">31255487</pub-id></citation></ref>
<ref id="B136"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kobayashi</surname> <given-names>J.</given-names></name> <name><surname>Hasegawa</surname> <given-names>T.</given-names></name> <name><surname>Sugeno</surname> <given-names>N.</given-names></name> <name><surname>Yoshida</surname> <given-names>S.</given-names></name> <name><surname>Akiyama</surname> <given-names>T.</given-names></name> <name><surname>Fujimori</surname> <given-names>K.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>Extracellular &#x003B1;-synuclein enters dopaminergic cells by modulating flotillin-1-assisted dopamine transporter endocytosis</article-title>. <source>FASEB J.</source> <volume>33</volume>, <fpage>10240</fpage>&#x02013;<lpage>10256</lpage>. <pub-id pub-id-type="doi">10.1096/fj.201802051r</pub-id><pub-id pub-id-type="pmid">31211923</pub-id></citation></ref>
<ref id="B137"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kordower</surname> <given-names>J. H.</given-names></name> <name><surname>Chu</surname> <given-names>Y.</given-names></name> <name><surname>Hauser</surname> <given-names>R. A.</given-names></name> <name><surname>Freeman</surname> <given-names>T. B.</given-names></name> <name><surname>Olanow</surname> <given-names>C. W.</given-names></name></person-group> (<year>2008</year>). <article-title>Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson&#x02019;s disease</article-title>. <source>Nat. Med.</source> <volume>14</volume>, <fpage>504</fpage>&#x02013;<lpage>506</lpage>. <pub-id pub-id-type="doi">10.1096/fj.201802051R</pub-id><pub-id pub-id-type="pmid">18391962</pub-id></citation></ref>
<ref id="B138"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Krasnoslobodtsev</surname> <given-names>A. V.</given-names></name> <name><surname>Peng</surname> <given-names>J.</given-names></name> <name><surname>Asiago</surname> <given-names>J. M.</given-names></name> <name><surname>Hindupur</surname> <given-names>J.</given-names></name> <name><surname>Rochet</surname> <given-names>J. C.</given-names></name> <name><surname>Lyubchenko</surname> <given-names>Y. L.</given-names></name></person-group> (<year>2012</year>). <article-title>Effect of spermidine on misfolding and interactions of &#x003B1;-synuclein</article-title>. <source>PLoS One</source> <volume>7</volume>:<fpage>e38099</fpage>. <pub-id pub-id-type="doi">10.1371/journal.pone.0038099</pub-id><pub-id pub-id-type="pmid">22662273</pub-id></citation></ref>
<ref id="B139"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kubler</surname> <given-names>D.</given-names></name> <name><surname>Wachter</surname> <given-names>T.</given-names></name> <name><surname>Cabanel</surname> <given-names>N.</given-names></name> <name><surname>Su</surname> <given-names>Z.</given-names></name> <name><surname>Turkheimer</surname> <given-names>F. E.</given-names></name> <name><surname>Dodel</surname> <given-names>R.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>Widespread microglial activation in multiple system atrophy</article-title>. <source>Mov. Disord.</source> <volume>34</volume>, <fpage>564</fpage>&#x02013;<lpage>568</lpage>. <pub-id pub-id-type="doi">10.1002/mds.27620</pub-id><pub-id pub-id-type="pmid">30726574</pub-id></citation></ref>
<ref id="B140"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lashuel</surname> <given-names>H. A.</given-names></name> <name><surname>Overk</surname> <given-names>C. R.</given-names></name> <name><surname>Oueslati</surname> <given-names>A.</given-names></name> <name><surname>Masliah</surname> <given-names>E.</given-names></name></person-group> (<year>2013</year>). <article-title>The many faces of &#x003B1;-synuclein: from structure and toxicity to therapeutic target</article-title>. <source>Nat. Rev. Neurosci.</source> <volume>14</volume>, <fpage>38</fpage>&#x02013;<lpage>48</lpage>. <pub-id pub-id-type="doi">10.1038/nrn3406</pub-id><pub-id pub-id-type="pmid">23254192</pub-id></citation></ref>
<ref id="B141"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lashuel</surname> <given-names>H. A.</given-names></name> <name><surname>Petre</surname> <given-names>B. M.</given-names></name> <name><surname>Wall</surname> <given-names>J.</given-names></name> <name><surname>Simon</surname> <given-names>M.</given-names></name> <name><surname>Nowak</surname> <given-names>R. J.</given-names></name> <name><surname>Walz</surname> <given-names>T.</given-names></name> <etal/></person-group>. (<year>2002</year>). <article-title>&#x003B1;-synuclein, especially the Parkinson&#x02019;s disease-associated mutants, forms pore-like annular and tubular protofibrils</article-title>. <source>J. Mol. Biol.</source> <volume>322</volume>, <fpage>1089</fpage>&#x02013;<lpage>1102</lpage>. <pub-id pub-id-type="doi">10.1016/s0022-2836(02)00735-0</pub-id><pub-id pub-id-type="pmid">12367530</pub-id></citation></ref>
<ref id="B142"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lau</surname> <given-names>A.</given-names></name> <name><surname>So</surname> <given-names>R. W. L.</given-names></name> <name><surname>Lau</surname> <given-names>H. H. C.</given-names></name> <name><surname>Sang</surname> <given-names>J. C.</given-names></name> <name><surname>Ruiz-Riquelme</surname> <given-names>A.</given-names></name> <name><surname>Fleck</surname> <given-names>S. C.</given-names></name> <etal/></person-group>. (<year>2020</year>). <article-title>&#x003B1;-Synuclein strains target distinct brain regions and cell types</article-title>. <source>Nat. Neurosci.</source> <volume>23</volume>, <fpage>21</fpage>&#x02013;<lpage>31</lpage>. <pub-id pub-id-type="doi">10.1038/s41593-019-0541-x</pub-id><pub-id pub-id-type="pmid">31792467</pub-id></citation></ref>
<ref id="B143"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Leak</surname> <given-names>R. K.</given-names></name> <name><surname>Frosch</surname> <given-names>M. P.</given-names></name> <name><surname>Beach</surname> <given-names>T. G.</given-names></name> <name><surname>Halliday</surname> <given-names>G. M.</given-names></name></person-group> (<year>2019</year>). <article-title>&#x003B1;-synuclein: prion or prion-like?</article-title> <source>Acta Neuropathol.</source> <volume>138</volume>, <fpage>509</fpage>&#x02013;<lpage>514</lpage>. <pub-id pub-id-type="doi">10.1007/s00401-019-02057-1</pub-id><pub-id pub-id-type="pmid">32857852</pub-id></citation></ref>
<ref id="B144"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lee</surname> <given-names>H. J.</given-names></name> <name><surname>Baek</surname> <given-names>S. M.</given-names></name> <name><surname>Ho</surname> <given-names>D. H.</given-names></name> <name><surname>Suk</surname> <given-names>J. E.</given-names></name> <name><surname>Cho</surname> <given-names>E. D.</given-names></name> <name><surname>Lee</surname> <given-names>S. J.</given-names></name></person-group> (<year>2011</year>). <article-title>Dopamine promotes formation and secretion of non-fibrillar &#x003B1;-synuclein oligomers</article-title>. <source>Exp. Mol. Med.</source> <volume>43</volume>, <fpage>216</fpage>&#x02013;<lpage>222</lpage>. <pub-id pub-id-type="doi">10.3858/emm.2011.43.4.026</pub-id><pub-id pub-id-type="pmid">21415592</pub-id></citation></ref>
<ref id="B145"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lee</surname> <given-names>H. J.</given-names></name> <name><surname>Khoshaghideh</surname> <given-names>F.</given-names></name> <name><surname>Patel</surname> <given-names>S.</given-names></name> <name><surname>Lee</surname> <given-names>S. J.</given-names></name></person-group> (<year>2004</year>). <article-title>Clearance of &#x003B1;-synuclein oligomeric intermediates <italic>via</italic> the lysosomal degradation pathway</article-title>. <source>J. Neurosci.</source> <volume>24</volume>, <fpage>1888</fpage>&#x02013;<lpage>1896</lpage>. <pub-id pub-id-type="doi">10.1523/jneurosci.3809-03.2004</pub-id><pub-id pub-id-type="pmid">14985429</pub-id></citation></ref>
<ref id="B146"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lee</surname> <given-names>H. J.</given-names></name> <name><surname>Suk</surname> <given-names>J. E.</given-names></name> <name><surname>Patrick</surname> <given-names>C.</given-names></name> <name><surname>Bae</surname> <given-names>E. J.</given-names></name> <name><surname>Cho</surname> <given-names>J. H.</given-names></name> <name><surname>Rho</surname> <given-names>S.</given-names></name> <etal/></person-group>. (<year>2010</year>). <article-title>Direct transfer of &#x003B1;-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies</article-title>. <source>J. Biol. Chem.</source> <volume>285</volume>, <fpage>9262</fpage>&#x02013;<lpage>9272</lpage>. <pub-id pub-id-type="doi">10.1074/jbc.m109.081125</pub-id><pub-id pub-id-type="pmid">20071342</pub-id></citation></ref>
<ref id="B147"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lee</surname> <given-names>V. M.</given-names></name> <name><surname>Trojanowski</surname> <given-names>J. Q.</given-names></name></person-group> (<year>2006</year>). <article-title>Mechanisms of Parkinson&#x02019;s disease linked to pathological &#x003B1;-synuclein: new targets for drug discovery</article-title>. <source>Neuron</source> <volume>52</volume>, <fpage>33</fpage>&#x02013;<lpage>38</lpage>. <pub-id pub-id-type="doi">10.1016/j.neuron.2006.09.026</pub-id><pub-id pub-id-type="pmid">17015225</pub-id></citation></ref>
<ref id="B148"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lema Tome</surname> <given-names>C. M.</given-names></name> <name><surname>Tyson</surname> <given-names>T.</given-names></name> <name><surname>Rey</surname> <given-names>N. L.</given-names></name> <name><surname>Grathwohl</surname> <given-names>S.</given-names></name> <name><surname>Britschgi</surname> <given-names>M.</given-names></name> <name><surname>Brundin</surname> <given-names>P.</given-names></name></person-group> (<year>2013</year>). <article-title>Inflammation and &#x003B1;-synuclein&#x02019;s prion-like behavior in Parkinson&#x02019;s disease&#x02013;is there a link?</article-title> <source>Mol. Neurobiol.</source> <volume>47</volume>, <fpage>561</fpage>&#x02013;<lpage>574</lpage>. <pub-id pub-id-type="doi">10.1007/s12035-012-8267-8</pub-id><pub-id pub-id-type="pmid">22544647</pub-id></citation></ref>
<ref id="B149"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Li</surname> <given-names>B.</given-names></name> <name><surname>Ge</surname> <given-names>P.</given-names></name> <name><surname>Murray</surname> <given-names>K. A.</given-names></name> <name><surname>Sheth</surname> <given-names>P.</given-names></name> <name><surname>Zhang</surname> <given-names>M.</given-names></name> <name><surname>Nair</surname> <given-names>G.</given-names></name> <etal/></person-group>. (<year>2018</year>). <article-title>Cryo-EM of full-length &#x003B1;-synuclein reveals fibril polymorphs with a common structural kernel</article-title>. <source>Nat. Commun.</source> <volume>9</volume>:<fpage>3609</fpage>. <pub-id pub-id-type="doi">10.1038/s41467-018-05971-2</pub-id><pub-id pub-id-type="pmid">30190461</pub-id></citation></ref>
<ref id="B150"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Li</surname> <given-names>J.</given-names></name> <name><surname>Zhu</surname> <given-names>M.</given-names></name> <name><surname>Rajamani</surname> <given-names>S.</given-names></name> <name><surname>Uversky</surname> <given-names>V. N.</given-names></name> <name><surname>Fink</surname> <given-names>A. L.</given-names></name></person-group> (<year>2004</year>). <article-title>Rifampicin inhibits &#x003B1;-synuclein fibrillation and disaggregates fibrils</article-title>. <source>Chem. Biol.</source> <volume>11</volume>, <fpage>1513</fpage>&#x02013;<lpage>1521</lpage>. <pub-id pub-id-type="doi">10.1016/j.chembiol.2004.08.025</pub-id><pub-id pub-id-type="pmid">15556002</pub-id></citation></ref>
<ref id="B151"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Li</surname> <given-names>J. Y.</given-names></name> <name><surname>Englund</surname> <given-names>E.</given-names></name> <name><surname>Holton</surname> <given-names>J. L.</given-names></name> <name><surname>Soulet</surname> <given-names>D.</given-names></name> <name><surname>Hagell</surname> <given-names>P.</given-names></name> <name><surname>Lees</surname> <given-names>A. J.</given-names></name> <etal/></person-group>. (<year>2008</year>). <article-title>Lewy bodies in grafted neurons in subjects with Parkinson&#x02019;s disease suggest host-to-graft disease propagation</article-title>. <source>Nat. Med.</source> <volume>14</volume>, <fpage>501</fpage>&#x02013;<lpage>503</lpage>. <pub-id pub-id-type="doi">10.1038/nm1746</pub-id><pub-id pub-id-type="pmid">18391963</pub-id></citation></ref>
<ref id="B152"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Li</surname> <given-names>W.</given-names></name> <name><surname>Englund</surname> <given-names>E.</given-names></name> <name><surname>Widner</surname> <given-names>H.</given-names></name> <name><surname>Mattsson</surname> <given-names>B.</given-names></name> <name><surname>Van Westen</surname> <given-names>D.</given-names></name> <name><surname>Latt</surname> <given-names>J.</given-names></name> <etal/></person-group>. (<year>2016</year>). <article-title>Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain</article-title>. <source>Proc. Natl. Acad. Sci. U S A</source> <volume>113</volume>, <fpage>6544</fpage>&#x02013;<lpage>6549</lpage>. <pub-id pub-id-type="doi">10.1073/pnas.1605245113</pub-id><pub-id pub-id-type="pmid">27140603</pub-id></citation></ref>
<ref id="B153"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Li</surname> <given-names>W.</given-names></name> <name><surname>West</surname> <given-names>N.</given-names></name> <name><surname>Colla</surname> <given-names>E.</given-names></name> <name><surname>Pletnikova</surname> <given-names>O.</given-names></name> <name><surname>Troncoso</surname> <given-names>J. C.</given-names></name> <name><surname>Marsh</surname> <given-names>L.</given-names></name> <etal/></person-group>. (<year>2005</year>). <article-title>Aggregation promoting C-terminal truncation of &#x003B1;-synuclein is a normal cellular process and is enhanced by the familial Parkinson&#x02019;s disease-linked mutations</article-title>. <source>Proc. Natl. Acad. Sci. U S A</source> <volume>102</volume>, <fpage>2162</fpage>&#x02013;<lpage>2167</lpage>. <pub-id pub-id-type="doi">10.1073/pnas.0406976102</pub-id><pub-id pub-id-type="pmid">15684072</pub-id></citation></ref>
<ref id="B154"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Li</surname> <given-names>W. W.</given-names></name> <name><surname>Yang</surname> <given-names>R.</given-names></name> <name><surname>Guo</surname> <given-names>J. C.</given-names></name> <name><surname>Ren</surname> <given-names>H. M.</given-names></name> <name><surname>Zha</surname> <given-names>X. L.</given-names></name> <name><surname>Cheng</surname> <given-names>J. S.</given-names></name> <etal/></person-group>. (<year>2007</year>). <article-title>Localization of &#x003B1;-synuclein to mitochondria within midbrain of mice</article-title>. <source>Neuroreport</source> <volume>18</volume>, <fpage>1543</fpage>&#x02013;<lpage>1546</lpage>. <pub-id pub-id-type="doi">10.1097/WNR.0b013e3282f03db4</pub-id><pub-id pub-id-type="pmid">17885598</pub-id></citation></ref>
<ref id="B155"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lindersson</surname> <given-names>E.</given-names></name> <name><surname>Beedholm</surname> <given-names>R.</given-names></name> <name><surname>Hojrup</surname> <given-names>P.</given-names></name> <name><surname>Moos</surname> <given-names>T.</given-names></name> <name><surname>Gai</surname> <given-names>W.</given-names></name> <name><surname>Hendil</surname> <given-names>K. B.</given-names></name> <etal/></person-group>. (<year>2004</year>). <article-title>Proteasomal inhibition by &#x003B1;-synuclein filaments and oligomers</article-title>. <source>J. Biol. Chem.</source> <volume>279</volume>, <fpage>12924</fpage>&#x02013;<lpage>12934</lpage>. <pub-id pub-id-type="doi">10.1074/jbc.M306390200</pub-id><pub-id pub-id-type="pmid">14711827</pub-id></citation></ref>
<ref id="B156"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lionnet</surname> <given-names>A.</given-names></name> <name><surname>Leclair-Visonneau</surname> <given-names>L.</given-names></name> <name><surname>Neunlist</surname> <given-names>M.</given-names></name> <name><surname>Murayama</surname> <given-names>S.</given-names></name> <name><surname>Takao</surname> <given-names>M.</given-names></name> <name><surname>Adler</surname> <given-names>C. H.</given-names></name> <etal/></person-group>. (<year>2018</year>). <article-title>Does Parkinson&#x02019;s disease start in the gut?</article-title> <source>Acta Neuropathol.</source> <volume>135</volume>, <fpage>1</fpage>&#x02013;<lpage>12</lpage>. <pub-id pub-id-type="doi">10.1007/s00401-017-1777-8</pub-id><pub-id pub-id-type="pmid">29039141</pub-id></citation></ref>
<ref id="B157"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Liu</surname> <given-names>C. Y.</given-names></name> <name><surname>Wang</surname> <given-names>X.</given-names></name> <name><surname>Liu</surname> <given-names>C.</given-names></name> <name><surname>Zhang</surname> <given-names>H. L.</given-names></name></person-group> (<year>2019</year>). <article-title>Pharmacological targeting of microglial activation: new therapeutic approach</article-title>. <source>Front. Cell. Neurosci.</source> <volume>13</volume>:<fpage>514</fpage>. <pub-id pub-id-type="doi">10.3389/fncel.2019.00514</pub-id><pub-id pub-id-type="pmid">31803024</pub-id></citation></ref>
<ref id="B158"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lohmann</surname> <given-names>S.</given-names></name> <name><surname>Bernis</surname> <given-names>M. E.</given-names></name> <name><surname>Tachu</surname> <given-names>B. J.</given-names></name> <name><surname>Ziemski</surname> <given-names>A.</given-names></name> <name><surname>Grigoletto</surname> <given-names>J.</given-names></name> <name><surname>Tamguney</surname> <given-names>G.</given-names></name></person-group> (<year>2019</year>). <article-title>Oral and intravenous transmission of &#x003B1;-synuclein fibrils to mice</article-title>. <source>Acta Neuropathol.</source> <volume>138</volume>, <fpage>515</fpage>&#x02013;<lpage>533</lpage>. <pub-id pub-id-type="doi">10.1007/s00401-019-02037-5</pub-id><pub-id pub-id-type="pmid">31230104</pub-id></citation></ref>
<ref id="B159"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lopes Da Fonseca</surname> <given-names>T.</given-names></name> <name><surname>Villar-Pique</surname> <given-names>A.</given-names></name> <name><surname>Outeiro</surname> <given-names>T. F.</given-names></name></person-group> (<year>2015</year>). <article-title>The interplay between &#x003B1;-synuclein clearance and spreading</article-title>. <source>Biomolecules</source> <volume>5</volume>, <fpage>435</fpage>&#x02013;<lpage>471</lpage>. <pub-id pub-id-type="doi">10.3390/biom5020435</pub-id><pub-id pub-id-type="pmid">25874605</pub-id></citation></ref>
<ref id="B160"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ludtmann</surname> <given-names>M. H. R.</given-names></name> <name><surname>Angelova</surname> <given-names>P. R.</given-names></name> <name><surname>Horrocks</surname> <given-names>M. H.</given-names></name> <name><surname>Choi</surname> <given-names>M. L.</given-names></name> <name><surname>Rodrigues</surname> <given-names>M.</given-names></name> <name><surname>Baev</surname> <given-names>A. Y.</given-names></name> <etal/></person-group>. (<year>2018</year>). <article-title>&#x003B1;-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson&#x02019;s disease</article-title>. <source>Nat. Commun.</source> <volume>9</volume>:<fpage>2293</fpage>. <pub-id pub-id-type="doi">10.1038/s41467-018-04422-2</pub-id><pub-id pub-id-type="pmid">29895861</pub-id></citation></ref>
<ref id="B161"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Luk</surname> <given-names>K. C.</given-names></name> <name><surname>Kehm</surname> <given-names>V.</given-names></name> <name><surname>Carroll</surname> <given-names>J.</given-names></name> <name><surname>Zhang</surname> <given-names>B.</given-names></name> <name><surname>O&#x02019;brien</surname> <given-names>P.</given-names></name> <name><surname>Trojanowski</surname> <given-names>J. Q.</given-names></name> <etal/></person-group>. (<year>2012a</year>). <article-title>Pathological &#x003B1;-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice</article-title>. <source>Science</source> <volume>338</volume>, <fpage>949</fpage>&#x02013;<lpage>953</lpage>. <pub-id pub-id-type="doi">10.1126/science.1227157</pub-id><pub-id pub-id-type="pmid">23161999</pub-id></citation></ref>
<ref id="B162"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Luk</surname> <given-names>K. C.</given-names></name> <name><surname>Kehm</surname> <given-names>V. M.</given-names></name> <name><surname>Zhang</surname> <given-names>B.</given-names></name> <name><surname>O&#x02019;brien</surname> <given-names>P.</given-names></name> <name><surname>Trojanowski</surname> <given-names>J. Q.</given-names></name> <name><surname>Lee</surname> <given-names>V. M.</given-names></name></person-group> (<year>2012b</year>). <article-title>Intracerebral inoculation of pathological &#x003B1;-synuclein initiates a rapidly progressive neurodegenerative &#x003B1;-synucleinopathy in mice</article-title>. <source>J. Exp. Med.</source> <volume>209</volume>, <fpage>975</fpage>&#x02013;<lpage>986</lpage>. <pub-id pub-id-type="doi">10.1084/jem.20112457</pub-id><pub-id pub-id-type="pmid">22508839</pub-id></citation></ref>
<ref id="B163"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Luk</surname> <given-names>K. C.</given-names></name> <name><surname>Song</surname> <given-names>C.</given-names></name> <name><surname>O&#x02019;Brien</surname> <given-names>P.</given-names></name> <name><surname>Stieber</surname> <given-names>A.</given-names></name> <name><surname>Branch</surname> <given-names>J. R.</given-names></name> <name><surname>Brunden</surname> <given-names>K. R.</given-names></name> <etal/></person-group>. (<year>2009</year>). <article-title>Exogenous &#x003B1;-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells</article-title>. <source>Proc. Natl. Acad. Sci. U S A</source> <volume>106</volume>, <fpage>20051</fpage>&#x02013;<lpage>20056</lpage>. <pub-id pub-id-type="doi">10.1073/pnas.0908005106</pub-id><pub-id pub-id-type="pmid">19892735</pub-id></citation></ref>
<ref id="B164"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Mahul-Mellier</surname> <given-names>A. L.</given-names></name> <name><surname>Burtscher</surname> <given-names>J.</given-names></name> <name><surname>Maharjan</surname> <given-names>N.</given-names></name> <name><surname>Weerens</surname> <given-names>L.</given-names></name> <name><surname>Croisier</surname> <given-names>M.</given-names></name> <name><surname>Kuttler</surname> <given-names>F.</given-names></name> <etal/></person-group>. (<year>2020</year>). <article-title>The process of Lewy body formation, rather than simply &#x003B1;-synuclein fibrillization, is one of the major drivers of neurodegeneration</article-title>. <source>Proc. Natl. Acad. Sci. U S A</source> <volume>117</volume>, <fpage>4971</fpage>&#x02013;<lpage>4982</lpage>. <pub-id pub-id-type="doi">10.1073/pnas.1913904117</pub-id><pub-id pub-id-type="pmid">32075919</pub-id></citation></ref>
<ref id="B165"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Malagelada</surname> <given-names>C.</given-names></name> <name><surname>Jin</surname> <given-names>Z. H.</given-names></name> <name><surname>Jackson-Lewis</surname> <given-names>V.</given-names></name> <name><surname>Przedborski</surname> <given-names>S.</given-names></name> <name><surname>Greene</surname> <given-names>L. A.</given-names></name></person-group> (<year>2010</year>). <article-title>Rapamycin protects against neuron death in <italic>in vitro</italic> and <italic>in vivo</italic> models of Parkinson&#x02019;s disease</article-title>. <source>J. Neurosci.</source> <volume>30</volume>, <fpage>1166</fpage>&#x02013;<lpage>1175</lpage>. <pub-id pub-id-type="doi">10.1523/jneurosci.3944-09.2010</pub-id><pub-id pub-id-type="pmid">20089925</pub-id></citation></ref>
<ref id="B166"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Mandel</surname> <given-names>R. J.</given-names></name> <name><surname>Marmion</surname> <given-names>D. J.</given-names></name> <name><surname>Kirik</surname> <given-names>D.</given-names></name> <name><surname>Chu</surname> <given-names>Y.</given-names></name> <name><surname>Heindel</surname> <given-names>C.</given-names></name> <name><surname>Mccown</surname> <given-names>T.</given-names></name> <etal/></person-group>. (<year>2017</year>). <article-title>Novel oligodendroglial &#x003B1;-synuclein viral vector models of multiple system atrophy: studies in rodents and nonhuman primates</article-title>. <source>Acta Neuropathol. Commun.</source> <volume>5</volume>:<fpage>47</fpage>. <pub-id pub-id-type="doi">10.1186/s40478-017-0451-7</pub-id><pub-id pub-id-type="pmid">28619074</pub-id></citation></ref>
<ref id="B167"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Mandler</surname> <given-names>M.</given-names></name> <name><surname>Valera</surname> <given-names>E.</given-names></name> <name><surname>Rockenstein</surname> <given-names>E.</given-names></name> <name><surname>Mante</surname> <given-names>M.</given-names></name> <name><surname>Weninger</surname> <given-names>H.</given-names></name> <name><surname>Patrick</surname> <given-names>C.</given-names></name> <etal/></person-group>. (<year>2015</year>). <article-title>Active immunization against &#x003B1;-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy</article-title>. <source>Mol. Neurodegener.</source> <volume>10</volume>:<fpage>10</fpage>. <pub-id pub-id-type="doi">10.1186/s13024-015-0008-9</pub-id><pub-id pub-id-type="pmid">25886309</pub-id></citation></ref>
<ref id="B168"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Mandler</surname> <given-names>M.</given-names></name> <name><surname>Valera</surname> <given-names>E.</given-names></name> <name><surname>Rockenstein</surname> <given-names>E.</given-names></name> <name><surname>Weninger</surname> <given-names>H.</given-names></name> <name><surname>Patrick</surname> <given-names>C.</given-names></name> <name><surname>Adame</surname> <given-names>A.</given-names></name> <etal/></person-group>. (<year>2014</year>). <article-title>Next-generation active immunization approach for synucleinopathies: implications for Parkinson&#x02019;s disease clinical trials</article-title>. <source>Acta Neuropathol.</source> <volume>127</volume>, <fpage>861</fpage>&#x02013;<lpage>879</lpage>. <pub-id pub-id-type="doi">10.1007/s00401-014-1256-4</pub-id><pub-id pub-id-type="pmid">24525765</pub-id></citation></ref>
<ref id="B169"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Manfredsson</surname> <given-names>F. P.</given-names></name> <name><surname>Luk</surname> <given-names>K. C.</given-names></name> <name><surname>Benskey</surname> <given-names>M. J.</given-names></name> <name><surname>Gezer</surname> <given-names>A.</given-names></name> <name><surname>Garcia</surname> <given-names>J.</given-names></name> <name><surname>Kuhn</surname> <given-names>N. C.</given-names></name> <etal/></person-group>. (<year>2018</year>). <article-title>Induction of &#x003B1;-synuclein pathology in the enteric nervous system of the rat and non-human primate results in gastrointestinal dysmotility and transient CNS pathology</article-title>. <source>Neurobiol. Dis.</source> <volume>112</volume>, <fpage>106</fpage>&#x02013;<lpage>118</lpage>. <pub-id pub-id-type="doi">10.1016/j.nbd.2018.01.008</pub-id><pub-id pub-id-type="pmid">29341898</pub-id></citation></ref>
<ref id="B170"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Mao</surname> <given-names>X.</given-names></name> <name><surname>Ou</surname> <given-names>M. T.</given-names></name> <name><surname>Karuppagounder</surname> <given-names>S. S.</given-names></name> <name><surname>Kam</surname> <given-names>T. I.</given-names></name> <name><surname>Yin</surname> <given-names>X.</given-names></name> <name><surname>Xiong</surname> <given-names>Y.</given-names></name> <etal/></person-group>. (<year>2016</year>). <article-title>Pathological &#x003B1;-synuclein transmission initiated by binding lymphocyte-activation gene 3</article-title>. <source>Science</source> <volume>353</volume>:<fpage>aah3374</fpage>. <pub-id pub-id-type="doi">10.1126/science.aah3374</pub-id><pub-id pub-id-type="pmid">27708076</pub-id></citation></ref>
<ref id="B171"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Maroteaux</surname> <given-names>L.</given-names></name> <name><surname>Campanelli</surname> <given-names>J. T.</given-names></name> <name><surname>Scheller</surname> <given-names>R. H.</given-names></name></person-group> (<year>1988</year>). <article-title>Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal</article-title>. <source>J. Neurosci.</source> <volume>8</volume>, <fpage>2804</fpage>&#x02013;<lpage>2815</lpage>. <pub-id pub-id-type="doi">10.1523/jneurosci.08-08-02804.1988</pub-id><pub-id pub-id-type="pmid">3411354</pub-id></citation></ref>
<ref id="B172"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Marreiros</surname> <given-names>R.</given-names></name> <name><surname>Muller-Schiffmann</surname> <given-names>A.</given-names></name> <name><surname>Trossbach</surname> <given-names>S. V.</given-names></name> <name><surname>Prikulis</surname> <given-names>I.</given-names></name> <name><surname>Hansch</surname> <given-names>S.</given-names></name> <name><surname>Weidtkamp-Peters</surname> <given-names>S.</given-names></name> <etal/></person-group>. (<year>2020</year>). <article-title>Disruption of cellular proteostasis by H1N1 influenza A virus causes &#x003B1;-synuclein aggregation</article-title>. <source>Proc. Natl. Acad. Sci. U S A</source> <volume>117</volume>, <fpage>6741</fpage>&#x02013;<lpage>6751</lpage>. <pub-id pub-id-type="doi">10.1073/pnas.1906466117</pub-id><pub-id pub-id-type="pmid">32152117</pub-id></citation></ref>
<ref id="B173"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Marti</surname> <given-names>M. J.</given-names></name> <name><surname>Tolosa</surname> <given-names>E.</given-names></name> <name><surname>Campdelacreu</surname> <given-names>J.</given-names></name></person-group> (<year>2003</year>). <article-title>Clinical overview of the synucleinopathies</article-title>. <source>Mov. Disord.</source> <volume>18</volume>, <fpage>S21</fpage>&#x02013;<lpage>S27</lpage>. <pub-id pub-id-type="doi">10.1002/mds.10559</pub-id><pub-id pub-id-type="pmid">14502652</pub-id></citation></ref>
<ref id="B174"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Masaracchia</surname> <given-names>C.</given-names></name> <name><surname>Hnida</surname> <given-names>M.</given-names></name> <name><surname>Gerhardt</surname> <given-names>E.</given-names></name> <name><surname>Lopes Da Fonseca</surname> <given-names>T.</given-names></name> <name><surname>Villar-Pique</surname> <given-names>A.</given-names></name> <name><surname>Branco</surname> <given-names>T.</given-names></name> <etal/></person-group>. (<year>2018</year>). <article-title>Membrane binding, internalization and sorting of &#x003B1;-synuclein in the cell</article-title>. <source>Acta Neuropathol. Commun.</source> <volume>6</volume>:<fpage>79</fpage>. <pub-id pub-id-type="doi">10.1186/s40478-018-0578-1</pub-id><pub-id pub-id-type="pmid">30107856</pub-id></citation></ref>
<ref id="B175"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Masliah</surname> <given-names>E.</given-names></name> <name><surname>Rockenstein</surname> <given-names>E.</given-names></name> <name><surname>Mante</surname> <given-names>M.</given-names></name> <name><surname>Crews</surname> <given-names>L.</given-names></name> <name><surname>Spencer</surname> <given-names>B.</given-names></name> <name><surname>Adame</surname> <given-names>A.</given-names></name> <etal/></person-group>. (<year>2011</year>). <article-title>Passive immunization reduces behavioral and neuropathological deficits in an &#x003B1;-synuclein transgenic model of Lewy body disease</article-title>. <source>PLoS One</source> <volume>6</volume>:<fpage>e19338</fpage>. <pub-id pub-id-type="doi">10.1371/journal.pone.0019338</pub-id><pub-id pub-id-type="pmid">21559417</pub-id></citation></ref>
<ref id="B176"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Masuda-Suzukake</surname> <given-names>M.</given-names></name> <name><surname>Nonaka</surname> <given-names>T.</given-names></name> <name><surname>Hosokawa</surname> <given-names>M.</given-names></name> <name><surname>Oikawa</surname> <given-names>T.</given-names></name> <name><surname>Arai</surname> <given-names>T.</given-names></name> <name><surname>Akiyama</surname> <given-names>H.</given-names></name> <etal/></person-group>. (<year>2013</year>). <article-title>Prion-like spreading of pathological &#x003B1;-synuclein in brain</article-title>. <source>Brain</source> <volume>136</volume>, <fpage>1128</fpage>&#x02013;<lpage>1138</lpage>. <pub-id pub-id-type="doi">10.1093/brain/awt037</pub-id><pub-id pub-id-type="pmid">23466394</pub-id></citation></ref>
<ref id="B177"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Mavroeidi</surname> <given-names>P.</given-names></name> <name><surname>Arvanitaki</surname> <given-names>F.</given-names></name> <name><surname>Karakitsou</surname> <given-names>A. K.</given-names></name> <name><surname>Vetsi</surname> <given-names>M.</given-names></name> <name><surname>Kloukina</surname> <given-names>I.</given-names></name> <name><surname>Zweckstetter</surname> <given-names>M.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>Endogenous oligodendroglial &#x003B1;-synuclein and TPPP/p25&#x003B1; orchestrate &#x003B1;-synuclein pathology in experimental multiple system atrophy models</article-title>. <source>Acta Neuropathol.</source> <volume>138</volume>, <fpage>415</fpage>&#x02013;<lpage>441</lpage>. <pub-id pub-id-type="doi">10.1007/s00401-019-02068-y</pub-id><pub-id pub-id-type="pmid">31011860</pub-id></citation></ref>
<ref id="B178"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>May</surname> <given-names>V. E.</given-names></name> <name><surname>Ettle</surname> <given-names>B.</given-names></name> <name><surname>Poehler</surname> <given-names>A. M.</given-names></name> <name><surname>Nuber</surname> <given-names>S.</given-names></name> <name><surname>Ubhi</surname> <given-names>K.</given-names></name> <name><surname>Rockenstein</surname> <given-names>E.</given-names></name> <etal/></person-group>. (<year>2014</year>). <article-title>&#x003B1;-Synuclein impairs oligodendrocyte progenitor maturation in multiple system atrophy</article-title>. <source>Neurobiol. Aging</source> <volume>35</volume>, <fpage>2357</fpage>&#x02013;<lpage>2368</lpage>. <pub-id pub-id-type="doi">10.1016/j.neurobiolaging.2014.02.028</pub-id><pub-id pub-id-type="pmid">24698767</pub-id></citation></ref>
<ref id="B179"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Mazzulli</surname> <given-names>J. R.</given-names></name> <name><surname>Zunke</surname> <given-names>F.</given-names></name> <name><surname>Isacson</surname> <given-names>O.</given-names></name> <name><surname>Studer</surname> <given-names>L.</given-names></name> <name><surname>Krainc</surname> <given-names>D.</given-names></name></person-group> (<year>2016</year>). <article-title>&#x003B1;-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models</article-title>. <source>Proc. Natl. Acad. Sci. U S A</source> <volume>113</volume>, <fpage>1931</fpage>&#x02013;<lpage>1936</lpage>. <pub-id pub-id-type="doi">10.1073/pnas.1520335113</pub-id><pub-id pub-id-type="pmid">26839413</pub-id></citation></ref>
<ref id="B181"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>McGeer</surname> <given-names>P. L.</given-names></name> <name><surname>Itagaki</surname> <given-names>S.</given-names></name> <name><surname>Boyes</surname> <given-names>B. E.</given-names></name> <name><surname>McGeer</surname> <given-names>E. G.</given-names></name></person-group> (<year>1988a</year>). <article-title>Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson&#x02019;s and Alzheimer&#x02019;s disease brains</article-title>. <source>Neurology</source> <volume>38</volume>, <fpage>1285</fpage>&#x02013;<lpage>1291</lpage>. <pub-id pub-id-type="doi">10.1212/wnl.38.8.1285</pub-id><pub-id pub-id-type="pmid">3399080</pub-id></citation></ref>
<ref id="B180"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>McGeer</surname> <given-names>P. L.</given-names></name> <name><surname>Itagaki</surname> <given-names>S.</given-names></name> <name><surname>McGeer</surname> <given-names>E. G.</given-names></name></person-group> (<year>1988b</year>). <article-title>Expression of the histocompatibility glycoprotein HLA-DR in neurological disease</article-title>. <source>Acta Neuropathol.</source> <volume>76</volume>, <fpage>550</fpage>&#x02013;<lpage>557</lpage>. <pub-id pub-id-type="doi">10.1007/bf00689592</pub-id><pub-id pub-id-type="pmid">2974227</pub-id></citation></ref>
<ref id="B182"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Meade</surname> <given-names>R. M.</given-names></name> <name><surname>Fairlie</surname> <given-names>D. P.</given-names></name> <name><surname>Mason</surname> <given-names>J. M.</given-names></name></person-group> (<year>2019</year>). <article-title>&#x003B1;-synuclein structure and Parkinson&#x02019;s disease&#x02014;lessons and emerging principles</article-title>. <source>Mol. Neurodegener.</source> <volume>14</volume>:<fpage>29</fpage>. <pub-id pub-id-type="doi">10.1186/s13024-019-0329-1</pub-id><pub-id pub-id-type="pmid">31331359</pub-id></citation></ref>
<ref id="B183"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Mendez</surname> <given-names>I.</given-names></name> <name><surname>Vinuela</surname> <given-names>A.</given-names></name> <name><surname>Astradsson</surname> <given-names>A.</given-names></name> <name><surname>Mukhida</surname> <given-names>K.</given-names></name> <name><surname>Hallett</surname> <given-names>P.</given-names></name> <name><surname>Robertson</surname> <given-names>H.</given-names></name> <etal/></person-group>. (<year>2008</year>). <article-title>Dopamine neurons implanted into people with Parkinson&#x02019;s disease survive without pathology for 14 years</article-title>. <source>Nat. Med.</source> <volume>14</volume>, <fpage>507</fpage>&#x02013;<lpage>509</lpage>. <pub-id pub-id-type="doi">10.1038/nm1752</pub-id><pub-id pub-id-type="pmid">18391961</pub-id></citation></ref>
<ref id="B184"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Miklossy</surname> <given-names>J.</given-names></name> <name><surname>Doudet</surname> <given-names>D. D.</given-names></name> <name><surname>Schwab</surname> <given-names>C.</given-names></name> <name><surname>Yu</surname> <given-names>S.</given-names></name> <name><surname>Mcgeer</surname> <given-names>E. G.</given-names></name> <name><surname>Mcgeer</surname> <given-names>P. L.</given-names></name></person-group> (<year>2006</year>). <article-title>Role of ICAM-1 in persisting inflammation in Parkinson disease and MPTP monkeys</article-title>. <source>Exp. Neurol.</source> <volume>197</volume>, <fpage>275</fpage>&#x02013;<lpage>283</lpage>. <pub-id pub-id-type="doi">10.1016/j.expneurol.2005.10.034</pub-id><pub-id pub-id-type="pmid">16336966</pub-id></citation></ref>
<ref id="B185"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Milanese</surname> <given-names>C.</given-names></name> <name><surname>Cerri</surname> <given-names>S.</given-names></name> <name><surname>Ulusoy</surname> <given-names>A.</given-names></name> <name><surname>Gornati</surname> <given-names>S. V.</given-names></name> <name><surname>Plat</surname> <given-names>A.</given-names></name> <name><surname>Gabriels</surname> <given-names>S.</given-names></name> <etal/></person-group>. (<year>2018</year>). <article-title>Activation of the DNA damage response <italic>in vivo</italic> in synucleinopathy models of Parkinson&#x02019;s disease</article-title>. <source>Cell Death Dis.</source> <volume>9</volume>:<fpage>818</fpage>. <pub-id pub-id-type="doi">10.1038/s41419-018-0848-7</pub-id><pub-id pub-id-type="pmid">30050065</pub-id></citation></ref>
<ref id="B186"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Mor</surname> <given-names>D. E.</given-names></name> <name><surname>Tsika</surname> <given-names>E.</given-names></name> <name><surname>Mazzulli</surname> <given-names>J. R.</given-names></name> <name><surname>Gould</surname> <given-names>N. S.</given-names></name> <name><surname>Kim</surname> <given-names>H.</given-names></name> <name><surname>Daniels</surname> <given-names>M. J.</given-names></name> <etal/></person-group>. (<year>2017</year>). <article-title>Dopamine induces soluble &#x003B1;-synuclein oligomers and nigrostriatal degeneration</article-title>. <source>Nat. Neurosci.</source> <volume>20</volume>, <fpage>1560</fpage>&#x02013;<lpage>1568</lpage>. <pub-id pub-id-type="doi">10.1038/nn.4641</pub-id><pub-id pub-id-type="pmid">28920936</pub-id></citation></ref>
<ref id="B187"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Mori</surname> <given-names>F.</given-names></name> <name><surname>Inenaga</surname> <given-names>C.</given-names></name> <name><surname>Yoshimoto</surname> <given-names>M.</given-names></name> <name><surname>Umezu</surname> <given-names>H.</given-names></name> <name><surname>Tanaka</surname> <given-names>R.</given-names></name> <name><surname>Takahashi</surname> <given-names>H.</given-names></name> <etal/></person-group>. (<year>2002</year>). <article-title>&#x003B1;-synuclein immunoreactivity in normal and neoplastic Schwann cells</article-title>. <source>Acta Neuropathol.</source> <volume>103</volume>, <fpage>145</fpage>&#x02013;<lpage>151</lpage>. <pub-id pub-id-type="doi">10.1007/s004010100443</pub-id><pub-id pub-id-type="pmid">11810180</pub-id></citation></ref>
<ref id="B188"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Nugent</surname> <given-names>E.</given-names></name> <name><surname>Kaminski</surname> <given-names>C. F.</given-names></name> <name><surname>Kaminski Schierle</surname> <given-names>G. S.</given-names></name></person-group> (<year>2017</year>). <article-title>Super-resolution imaging of &#x003B1;-synuclein polymorphisms and their potential role in neurodegeneration</article-title>. <source>Integr. Biol.</source> <volume>9</volume>, <fpage>206</fpage>&#x02013;<lpage>210</lpage>. <pub-id pub-id-type="doi">10.1039/c6ib00206d</pub-id><pub-id pub-id-type="pmid">28180219</pub-id></citation></ref>
<ref id="B189"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Olanow</surname> <given-names>C. W.</given-names></name> <name><surname>Perl</surname> <given-names>D. P.</given-names></name> <name><surname>Demartino</surname> <given-names>G. N.</given-names></name> <name><surname>Mcnaught</surname> <given-names>K. S.</given-names></name></person-group> (<year>2004</year>). <article-title>Lewy-body formation is an aggresome-related process: a hypothesis</article-title>. <source>Lancet Neurol.</source> <volume>3</volume>, <fpage>496</fpage>&#x02013;<lpage>503</lpage>. <pub-id pub-id-type="doi">10.1016/s1474-4422(04)00827-0</pub-id><pub-id pub-id-type="pmid">15261611</pub-id></citation></ref>
<ref id="B190"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Olanow</surname> <given-names>C. W.</given-names></name> <name><surname>Savolainen</surname> <given-names>M.</given-names></name> <name><surname>Chu</surname> <given-names>Y.</given-names></name> <name><surname>Halliday</surname> <given-names>G. M.</given-names></name> <name><surname>Kordower</surname> <given-names>J. H.</given-names></name></person-group> (<year>2019</year>). <article-title>Temporal evolution of microglia and &#x003B1;-synuclein accumulation following foetal grafting in Parkinson&#x02019;s disease</article-title>. <source>Brain</source> <volume>142</volume>, <fpage>1690</fpage>&#x02013;<lpage>1700</lpage>. <pub-id pub-id-type="doi">10.1093/brain/awz104</pub-id><pub-id pub-id-type="pmid">31056668</pub-id></citation></ref>
<ref id="B191"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ono</surname> <given-names>K.</given-names></name> <name><surname>Takahashi</surname> <given-names>R.</given-names></name> <name><surname>Ikeda</surname> <given-names>T.</given-names></name> <name><surname>Yamada</surname> <given-names>M.</given-names></name></person-group> (<year>2012</year>). <article-title>Cross-seeding effects of amyloid &#x003B2;-protein and &#x003B1;-synuclein</article-title>. <source>J. Neurochem.</source> <volume>122</volume>, <fpage>883</fpage>&#x02013;<lpage>890</lpage>. <pub-id pub-id-type="doi">10.1111/j.1471-4159.2012.07847.x</pub-id><pub-id pub-id-type="pmid">22734715</pub-id></citation></ref>
<ref id="B192"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Orimo</surname> <given-names>S.</given-names></name> <name><surname>Uchihara</surname> <given-names>T.</given-names></name> <name><surname>Nakamura</surname> <given-names>A.</given-names></name> <name><surname>Mori</surname> <given-names>F.</given-names></name> <name><surname>Kakita</surname> <given-names>A.</given-names></name> <name><surname>Wakabayashi</surname> <given-names>K.</given-names></name> <etal/></person-group>. (<year>2008</year>). <article-title>Axonal &#x003B1;-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in Parkinson&#x02019;s disease</article-title>. <source>Brain</source> <volume>131</volume>, <fpage>642</fpage>&#x02013;<lpage>650</lpage>. <pub-id pub-id-type="doi">10.1093/brain/awm302</pub-id><pub-id pub-id-type="pmid">18079166</pub-id></citation></ref>
<ref id="B193"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Orme</surname> <given-names>T.</given-names></name> <name><surname>Guerreiro</surname> <given-names>R.</given-names></name> <name><surname>Bras</surname> <given-names>J.</given-names></name></person-group> (<year>2018</year>). <article-title>The genetics of dementia with Lewy bodies: current understanding and future directions</article-title>. <source>Curr. Neurol. Neurosci. Rep.</source> <volume>18</volume>:<fpage>67</fpage>. <pub-id pub-id-type="doi">10.1007/s11910-018-0874-y</pub-id><pub-id pub-id-type="pmid">30097731</pub-id></citation></ref>
<ref id="B194"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Outeiro</surname> <given-names>T. F.</given-names></name> <name><surname>Koss</surname> <given-names>D. J.</given-names></name> <name><surname>Erskine</surname> <given-names>D.</given-names></name> <name><surname>Walker</surname> <given-names>L.</given-names></name> <name><surname>Kurzawa-Akanbi</surname> <given-names>M.</given-names></name> <name><surname>Burn</surname> <given-names>D.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>Dementia with Lewy bodies: an update and outlook</article-title>. <source>Mol. Neurodegener.</source> <volume>14</volume>:<fpage>5</fpage>. <pub-id pub-id-type="doi">10.1186/s13024-019-0306-8</pub-id><pub-id pub-id-type="pmid">30665447</pub-id></citation></ref>
<ref id="B195"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ozawa</surname> <given-names>T.</given-names></name> <name><surname>Paviour</surname> <given-names>D.</given-names></name> <name><surname>Quinn</surname> <given-names>N. P.</given-names></name> <name><surname>Josephs</surname> <given-names>K. A.</given-names></name> <name><surname>Sangha</surname> <given-names>H.</given-names></name> <name><surname>Kilford</surname> <given-names>L.</given-names></name> <etal/></person-group>. (<year>2004</year>). <article-title>The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations</article-title>. <source>Brain</source> <volume>127</volume>, <fpage>2657</fpage>&#x02013;<lpage>2671</lpage>. <pub-id pub-id-type="doi">10.1093/brain/awh303</pub-id><pub-id pub-id-type="pmid">15509623</pub-id></citation></ref>
<ref id="B196"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Paiva</surname> <given-names>I.</given-names></name> <name><surname>Pinho</surname> <given-names>R.</given-names></name> <name><surname>Pavlou</surname> <given-names>M. A.</given-names></name> <name><surname>Hennion</surname> <given-names>M.</given-names></name> <name><surname>Wales</surname> <given-names>P.</given-names></name> <name><surname>Schutz</surname> <given-names>A. L.</given-names></name> <etal/></person-group>. (<year>2017</year>). <article-title>Sodium butyrate rescues dopaminergic cells from &#x003B1;-synuclein-induced transcriptional deregulation and DNA damage</article-title>. <source>Hum. Mol. Genet.</source> <volume>26</volume>, <fpage>2231</fpage>&#x02013;<lpage>2246</lpage>. <pub-id pub-id-type="doi">10.1093/hmg/ddx114</pub-id><pub-id pub-id-type="pmid">28369321</pub-id></citation></ref>
<ref id="B197"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Parihar</surname> <given-names>M. S.</given-names></name> <name><surname>Parihar</surname> <given-names>A.</given-names></name> <name><surname>Fujita</surname> <given-names>M.</given-names></name> <name><surname>Hashimoto</surname> <given-names>M.</given-names></name> <name><surname>Ghafourifar</surname> <given-names>P.</given-names></name></person-group> (<year>2008</year>). <article-title>Mitochondrial association of &#x003B1;-synuclein causes oxidative stress</article-title>. <source>Cell Mol. Life Sci.</source> <volume>65</volume>, <fpage>1272</fpage>&#x02013;<lpage>1284</lpage>. <pub-id pub-id-type="doi">10.1007/s00018-008-7589-1</pub-id><pub-id pub-id-type="pmid">18322646</pub-id></citation></ref>
<ref id="B198"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Park</surname> <given-names>H. J.</given-names></name> <name><surname>Oh</surname> <given-names>S. H.</given-names></name> <name><surname>Kim</surname> <given-names>H. N.</given-names></name> <name><surname>Jung</surname> <given-names>Y. J.</given-names></name> <name><surname>Lee</surname> <given-names>P. H.</given-names></name></person-group> (<year>2016</year>). <article-title>Mesenchymal stem cells enhance &#x003B1;-synuclein clearance <italic>via</italic> M2 microglia polarization in experimental and human parkinsonian disorder</article-title>. <source>Acta Neuropathol.</source> <volume>132</volume>, <fpage>685</fpage>&#x02013;<lpage>701</lpage>. <pub-id pub-id-type="doi">10.1007/s00401-016-1605-6</pub-id><pub-id pub-id-type="pmid">27497943</pub-id></citation></ref>
<ref id="B199"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Park</surname> <given-names>J. H.</given-names></name> <name><surname>Burgess</surname> <given-names>J. D.</given-names></name> <name><surname>Faroqi</surname> <given-names>A. H.</given-names></name> <name><surname>Demeo</surname> <given-names>N. N.</given-names></name> <name><surname>Fiesel</surname> <given-names>F. C.</given-names></name> <name><surname>Springer</surname> <given-names>W.</given-names></name> <etal/></person-group>. (<year>2020</year>). <article-title>&#x003B1;-synuclein-induced mitochondrial dysfunction is mediated <italic>via</italic> a sirtuin 3-dependent pathway</article-title>. <source>Mol. Neurodegener.</source> <volume>15</volume>:<fpage>5</fpage>. <pub-id pub-id-type="doi">10.1101/357624</pub-id><pub-id pub-id-type="pmid">31931835</pub-id></citation></ref>
<ref id="B200"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Paumier</surname> <given-names>K. L.</given-names></name> <name><surname>Luk</surname> <given-names>K. C.</given-names></name> <name><surname>Manfredsson</surname> <given-names>F. P.</given-names></name> <name><surname>Kanaan</surname> <given-names>N. M.</given-names></name> <name><surname>Lipton</surname> <given-names>J. W.</given-names></name> <name><surname>Collier</surname> <given-names>T. J.</given-names></name> <etal/></person-group>. (<year>2015</year>). <article-title>Intrastriatal injection of pre-formed mouse &#x003B1;-synuclein fibrils into rats triggers &#x003B1;-synuclein pathology and bilateral nigrostriatal degeneration</article-title>. <source>Neurobiol. Dis.</source> <volume>82</volume>, <fpage>185</fpage>&#x02013;<lpage>199</lpage>. <pub-id pub-id-type="doi">10.1016/j.nbd.2015.06.003</pub-id><pub-id pub-id-type="pmid">26093169</pub-id></citation></ref>
<ref id="B201"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Peelaerts</surname> <given-names>W.</given-names></name> <name><surname>Bousset</surname> <given-names>L.</given-names></name> <name><surname>Van Der Perren</surname> <given-names>A.</given-names></name> <name><surname>Moskalyuk</surname> <given-names>A.</given-names></name> <name><surname>Pulizzi</surname> <given-names>R.</given-names></name> <name><surname>Giugliano</surname> <given-names>M.</given-names></name> <etal/></person-group>. (<year>2015</year>). <article-title>&#x003B1;-Synuclein strains cause distinct synucleinopathies after local and systemic administration</article-title>. <source>Nature</source> <volume>522</volume>, <fpage>340</fpage>&#x02013;<lpage>344</lpage>. <pub-id pub-id-type="doi">10.1038/nature14547</pub-id><pub-id pub-id-type="pmid">26061766</pub-id></citation></ref>
<ref id="B203"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Peng</surname> <given-names>C.</given-names></name> <name><surname>Gathagan</surname> <given-names>R. J.</given-names></name> <name><surname>Covell</surname> <given-names>D. J.</given-names></name> <name><surname>Medellin</surname> <given-names>C.</given-names></name> <name><surname>Stieber</surname> <given-names>A.</given-names></name> <name><surname>Robinson</surname> <given-names>J. L.</given-names></name> <etal/></person-group>. (<year>2018a</year>). <article-title>Cellular milieu imparts distinct pathological &#x003B1;-synuclein strains in alpha-synucleinopathies</article-title>. <source>Nature</source> <volume>557</volume>, <fpage>558</fpage>&#x02013;<lpage>563</lpage>. <pub-id pub-id-type="doi">10.1038/s41586-018-0104-4</pub-id><pub-id pub-id-type="pmid">29743672</pub-id></citation></ref>
<ref id="B202"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Peng</surname> <given-names>C.</given-names></name> <name><surname>Gathagan</surname> <given-names>R. J.</given-names></name> <name><surname>Lee</surname> <given-names>V. M.</given-names></name></person-group> (<year>2018b</year>). <article-title>Distinct &#x003B1;-Synuclein strains and implications for heterogeneity among alpha-Synucleinopathies</article-title>. <source>Neurobiol. Dis.</source> <volume>109</volume>, <fpage>209</fpage>&#x02013;<lpage>218</lpage>. <pub-id pub-id-type="doi">10.1016/j.nbd.2017.07.018</pub-id><pub-id pub-id-type="pmid">28751258</pub-id></citation></ref>
<ref id="B204"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Perez</surname> <given-names>R. G.</given-names></name> <name><surname>Hastings</surname> <given-names>T. G.</given-names></name></person-group> (<year>2004</year>). <article-title>Could a loss of &#x003B1;-synuclein function put dopaminergic neurons at risk?</article-title> <source>J. Neurochem.</source> <volume>89</volume>, <fpage>1318</fpage>&#x02013;<lpage>1324</lpage>. <pub-id pub-id-type="doi">10.1111/j.1471-4159.2004.02423.x</pub-id><pub-id pub-id-type="pmid">15189334</pub-id></citation></ref>
<ref id="B205"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Perrino</surname> <given-names>G.</given-names></name> <name><surname>Wilson</surname> <given-names>C.</given-names></name> <name><surname>Santorelli</surname> <given-names>M.</given-names></name> <name><surname>Di Bernardo</surname> <given-names>D.</given-names></name></person-group> (<year>2019</year>). <article-title>Quantitative characterization of &#x003B1;-synuclein aggregation in living cells through automated microfluidics feedback control</article-title>. <source>Cell Rep.</source> <volume>27</volume>, <fpage>916.e5</fpage>&#x02013;<lpage>927.e5</lpage>. <pub-id pub-id-type="doi">10.1016/j.celrep.2019.03.081</pub-id><pub-id pub-id-type="pmid">30995486</pub-id></citation></ref>
<ref id="B206"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Petrucelli</surname> <given-names>L.</given-names></name> <name><surname>O&#x02019;Farrell</surname> <given-names>C.</given-names></name> <name><surname>Lockhart</surname> <given-names>P. J.</given-names></name> <name><surname>Baptista</surname> <given-names>M.</given-names></name> <name><surname>Kehoe</surname> <given-names>K.</given-names></name> <name><surname>Vink</surname> <given-names>L.</given-names></name> <etal/></person-group>. (<year>2002</year>). <article-title>Parkin protects against the toxicity associated with mutant &#x003B1;-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons</article-title>. <source>Neuron</source> <volume>36</volume>, <fpage>1007</fpage>&#x02013;<lpage>1019</lpage>. <pub-id pub-id-type="doi">10.1016/s0896-6273(02)01125-x</pub-id><pub-id pub-id-type="pmid">12495618</pub-id></citation></ref>
<ref id="B207"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Phan</surname> <given-names>J. A.</given-names></name> <name><surname>Stokholm</surname> <given-names>K.</given-names></name> <name><surname>Zareba-Paslawska</surname> <given-names>J.</given-names></name> <name><surname>Jakobsen</surname> <given-names>S.</given-names></name> <name><surname>Vang</surname> <given-names>K.</given-names></name> <name><surname>Gjedde</surname> <given-names>A.</given-names></name> <etal/></person-group>. (<year>2017</year>). <article-title>Early synaptic dysfunction induced by &#x003B1;-synuclein in a rat model of Parkinson&#x02019;s disease</article-title>. <source>Sci. Rep.</source> <volume>7</volume>:<fpage>6363</fpage>. <pub-id pub-id-type="doi">10.1038/s41598-017-06724-9</pub-id><pub-id pub-id-type="pmid">28743955</pub-id></citation></ref>
<ref id="B208"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Pinho</surname> <given-names>R.</given-names></name> <name><surname>Paiva</surname> <given-names>I.</given-names></name> <name><surname>Jercic</surname> <given-names>K. G.</given-names></name> <name><surname>Fonseca-Ornelas</surname> <given-names>L.</given-names></name> <name><surname>Gerhardt</surname> <given-names>E.</given-names></name> <name><surname>Fahlbusch</surname> <given-names>C.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>Nuclear localization and phosphorylation modulate pathological effects of &#x003B1;-synuclein</article-title>. <source>Hum. Mol. Genet.</source> <volume>28</volume>, <fpage>31</fpage>&#x02013;<lpage>50</lpage>. <pub-id pub-id-type="doi">10.1093/hmg/ddy326</pub-id><pub-id pub-id-type="pmid">30219847</pub-id></citation></ref>
<ref id="B209"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Polymeropoulos</surname> <given-names>M. H.</given-names></name> <name><surname>Higgins</surname> <given-names>J. J.</given-names></name> <name><surname>Golbe</surname> <given-names>L. I.</given-names></name> <name><surname>Johnson</surname> <given-names>W. G.</given-names></name> <name><surname>Ide</surname> <given-names>S. E.</given-names></name> <name><surname>Di Iorio</surname> <given-names>G.</given-names></name> <etal/></person-group>. (<year>1996</year>). <article-title>Mapping of a gene for Parkinson&#x02019;s disease to chromosome 4q21&#x02013;q23</article-title>. <source>Science</source> <volume>274</volume>, <fpage>1197</fpage>&#x02013;<lpage>1199</lpage>. <pub-id pub-id-type="doi">10.1126/science.274.5290.1197</pub-id><pub-id pub-id-type="pmid">8895469</pub-id></citation></ref>
<ref id="B210"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Polymeropoulos</surname> <given-names>M. H.</given-names></name> <name><surname>Lavedan</surname> <given-names>C.</given-names></name> <name><surname>Leroy</surname> <given-names>E.</given-names></name> <name><surname>Ide</surname> <given-names>S. E.</given-names></name> <name><surname>Dehejia</surname> <given-names>A.</given-names></name> <name><surname>Dutra</surname> <given-names>A.</given-names></name> <etal/></person-group>. (<year>1997</year>). <article-title>Mutation in the &#x003B1;-synuclein gene identified in families with Parkinson&#x02019;s disease</article-title>. <source>Science</source> <volume>276</volume>, <fpage>2045</fpage>&#x02013;<lpage>2047</lpage>. <pub-id pub-id-type="doi">10.1126/science.276.5321.2045</pub-id><pub-id pub-id-type="pmid">9197268</pub-id></citation></ref>
<ref id="B211"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Post</surname> <given-names>M. R.</given-names></name> <name><surname>Lieberman</surname> <given-names>O. J.</given-names></name> <name><surname>Mosharov</surname> <given-names>E. V.</given-names></name></person-group> (<year>2018</year>). <article-title>Can interactions between &#x003B1;-synuclein, dopamine and calcium explain selective neurodegeneration in Parkinson&#x02019;s disease?</article-title> <source>Front. Neurosci.</source> <volume>12</volume>:<fpage>161</fpage>. <pub-id pub-id-type="doi">10.3389/fnins.2018.00161</pub-id><pub-id pub-id-type="pmid">29593491</pub-id></citation></ref>
<ref id="B212"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Price</surname> <given-names>D. L.</given-names></name> <name><surname>Koike</surname> <given-names>M. A.</given-names></name> <name><surname>Khan</surname> <given-names>A.</given-names></name> <name><surname>Wrasidlo</surname> <given-names>W.</given-names></name> <name><surname>Rockenstein</surname> <given-names>E.</given-names></name> <name><surname>Masliah</surname> <given-names>E.</given-names></name> <etal/></person-group>. (<year>2018</year>). <article-title>The small molecule &#x003B1;-synuclein misfolding inhibitor, NPT200&#x02013;11, produces multiple benefits in an animal model of Parkinson&#x02019;s disease</article-title>. <source>Sci. Rep.</source> <volume>8</volume>:<fpage>16165</fpage>. <pub-id pub-id-type="doi">10.1038/s41598-018-34490-9</pub-id><pub-id pub-id-type="pmid">30385782</pub-id></citation></ref>
<ref id="B213"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Pringsheim</surname> <given-names>T.</given-names></name> <name><surname>Jette</surname> <given-names>N.</given-names></name> <name><surname>Frolkis</surname> <given-names>A.</given-names></name> <name><surname>Steeves</surname> <given-names>T. D.</given-names></name></person-group> (<year>2014</year>). <article-title>The prevalence of Parkinson&#x02019;s disease: a systematic review and meta-analysis</article-title>. <source>Mov. Disord.</source> <volume>29</volume>, <fpage>1583</fpage>&#x02013;<lpage>1590</lpage>. <pub-id pub-id-type="doi">10.1002/mds.25945</pub-id><pub-id pub-id-type="pmid">24976103</pub-id></citation></ref>
<ref id="B214"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Prusiner</surname> <given-names>S. B.</given-names></name></person-group> (<year>1982</year>). <article-title>Novel proteinaceous infectious particles cause scrapie</article-title>. <source>Science</source> <volume>216</volume>, <fpage>136</fpage>&#x02013;<lpage>144</lpage>. <pub-id pub-id-type="doi">10.1126/science.6801762</pub-id><pub-id pub-id-type="pmid">6801762</pub-id></citation></ref>
<ref id="B215"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Prusiner</surname> <given-names>S. B.</given-names></name></person-group> (<year>1998</year>). <article-title>Prions</article-title>. <source>Proc. Natl. Acad. Sci. U S A</source> <volume>95</volume>, <fpage>13363</fpage>&#x02013;<lpage>13383</lpage>. <pub-id pub-id-type="doi">10.1073/pnas.95.23.13363</pub-id><pub-id pub-id-type="pmid">9811807</pub-id></citation></ref>
<ref id="B216"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Radford</surname> <given-names>R.</given-names></name> <name><surname>Rcom-H&#x02019;cheo-Gauthier</surname> <given-names>A.</given-names></name> <name><surname>Wong</surname> <given-names>M. B.</given-names></name> <name><surname>Eaton</surname> <given-names>E. D.</given-names></name> <name><surname>Quilty</surname> <given-names>M.</given-names></name> <name><surname>Blizzard</surname> <given-names>C.</given-names></name> <etal/></person-group>. (<year>2015</year>). <article-title>The degree of astrocyte activation in multiple system atrophy is inversely proportional to the distance to &#x003B1;-synuclein inclusions</article-title>. <source>Mol. Cell. Neurosci.</source> <volume>65</volume>, <fpage>68</fpage>&#x02013;<lpage>81</lpage>. <pub-id pub-id-type="doi">10.1016/j.mcn.2015.02.015</pub-id><pub-id pub-id-type="pmid">25731829</pub-id></citation></ref>
<ref id="B217"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Rajput</surname> <given-names>A. H.</given-names></name> <name><surname>Ferguson</surname> <given-names>L. W.</given-names></name> <name><surname>Robinson</surname> <given-names>C. A.</given-names></name> <name><surname>Guella</surname> <given-names>I.</given-names></name> <name><surname>Farrer</surname> <given-names>M. J.</given-names></name> <name><surname>Rajput</surname> <given-names>A.</given-names></name></person-group> (<year>2016</year>). <article-title>Conjugal parkinsonism&#x02014;clinical, pathology and genetic study. No evidence of person-to-person transmission</article-title>. <source>Parkinsonism Relat. Disord.</source> <volume>31</volume>, <fpage>87</fpage>&#x02013;<lpage>90</lpage>. <pub-id pub-id-type="doi">10.1016/j.parkreldis.2016.07.011</pub-id><pub-id pub-id-type="pmid">27481034</pub-id></citation></ref>
<ref id="B218"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Recasens</surname> <given-names>A.</given-names></name> <name><surname>Carballo-Carbajal</surname> <given-names>I.</given-names></name> <name><surname>Parent</surname> <given-names>A.</given-names></name> <name><surname>Bove</surname> <given-names>J.</given-names></name> <name><surname>Gelpi</surname> <given-names>E.</given-names></name> <name><surname>Tolosa</surname> <given-names>E.</given-names></name> <etal/></person-group>. (<year>2018</year>). <article-title>Lack of pathogenic potential of peripheral &#x003B1;-synuclein aggregates from Parkinson&#x02019;s disease patients</article-title>. <source>Acta Neuropathol. Commun.</source> <volume>6</volume>:<fpage>8</fpage>. <pub-id pub-id-type="doi">10.1186/s40478-018-0509-1</pub-id><pub-id pub-id-type="pmid">29422109</pub-id></citation></ref>
<ref id="B219"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Recasens</surname> <given-names>A.</given-names></name> <name><surname>Dehay</surname> <given-names>B.</given-names></name> <name><surname>Bove</surname> <given-names>J.</given-names></name> <name><surname>Carballo-Carbajal</surname> <given-names>I.</given-names></name> <name><surname>Dovero</surname> <given-names>S.</given-names></name> <name><surname>Perez-Villalba</surname> <given-names>A.</given-names></name> <etal/></person-group>. (<year>2014</year>). <article-title>Lewy body extracts from Parkinson disease brains trigger &#x003B1;-synuclein pathology and neurodegeneration in mice and monkeys</article-title>. <source>Ann. Neurol.</source> <volume>75</volume>, <fpage>351</fpage>&#x02013;<lpage>362</lpage>. <pub-id pub-id-type="doi">10.1002/ana.24066</pub-id><pub-id pub-id-type="pmid">24243558</pub-id></citation></ref>
<ref id="B220"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Reeve</surname> <given-names>A. K.</given-names></name> <name><surname>Ludtmann</surname> <given-names>M. H.</given-names></name> <name><surname>Angelova</surname> <given-names>P. R.</given-names></name> <name><surname>Simcox</surname> <given-names>E. M.</given-names></name> <name><surname>Horrocks</surname> <given-names>M. H.</given-names></name> <name><surname>Klenerman</surname> <given-names>D.</given-names></name> <etal/></person-group>. (<year>2015</year>). <article-title>Aggregated &#x003B1;-synuclein and complex I deficiency: exploration of their relationship in differentiated neurons</article-title>. <source>Cell Death Dis.</source> <volume>6</volume>:<fpage>e1820</fpage>. <pub-id pub-id-type="doi">10.1038/cddis.2015.166</pub-id><pub-id pub-id-type="pmid">26181201</pub-id></citation></ref>
<ref id="B221"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Rey</surname> <given-names>N. L.</given-names></name> <name><surname>Bousset</surname> <given-names>L.</given-names></name> <name><surname>George</surname> <given-names>S.</given-names></name> <name><surname>Madaj</surname> <given-names>Z.</given-names></name> <name><surname>Meyerdirk</surname> <given-names>L.</given-names></name> <name><surname>Schulz</surname> <given-names>E.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>&#x003B1;-Synuclein conformational strains spread, seed and target neuronal cells differentially after injection into the olfactory bulb</article-title>. <source>Acta Neuropathol. Commun.</source> <volume>7</volume>:<fpage>221</fpage>. <pub-id pub-id-type="doi">10.1186/s40478-019-0859-3</pub-id><pub-id pub-id-type="pmid">31888771</pub-id></citation></ref>
<ref id="B222"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Rey</surname> <given-names>N. L.</given-names></name> <name><surname>George</surname> <given-names>S.</given-names></name> <name><surname>Steiner</surname> <given-names>J. A.</given-names></name> <name><surname>Madaj</surname> <given-names>Z.</given-names></name> <name><surname>Luk</surname> <given-names>K. C.</given-names></name> <name><surname>Trojanowski</surname> <given-names>J. Q.</given-names></name> <etal/></person-group>. (<year>2018</year>). <article-title>Spread of aggregates after olfactory bulb injection of &#x003B1;-synuclein fibrils is associated with early neuronal loss and is reduced long term</article-title>. <source>Acta Neuropathol.</source> <volume>135</volume>, <fpage>65</fpage>&#x02013;<lpage>83</lpage>. <pub-id pub-id-type="doi">10.1007/s00401-017-1792-9</pub-id><pub-id pub-id-type="pmid">29209768</pub-id></citation></ref>
<ref id="B223"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Reyes</surname> <given-names>J. F.</given-names></name> <name><surname>Rey</surname> <given-names>N. L.</given-names></name> <name><surname>Bousset</surname> <given-names>L.</given-names></name> <name><surname>Melki</surname> <given-names>R.</given-names></name> <name><surname>Brundin</surname> <given-names>P.</given-names></name> <name><surname>Angot</surname> <given-names>E.</given-names></name></person-group> (<year>2014</year>). <article-title>&#x003B1;-synuclein transfers from neurons to oligodendrocytes</article-title>. <source>Glia</source> <volume>62</volume>, <fpage>387</fpage>&#x02013;<lpage>398</lpage>. <pub-id pub-id-type="doi">10.1002/glia.22611</pub-id><pub-id pub-id-type="pmid">24382629</pub-id></citation></ref>
<ref id="B224"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Rott</surname> <given-names>R.</given-names></name> <name><surname>Szargel</surname> <given-names>R.</given-names></name> <name><surname>Shani</surname> <given-names>V.</given-names></name> <name><surname>Hamza</surname> <given-names>H.</given-names></name> <name><surname>Savyon</surname> <given-names>M.</given-names></name> <name><surname>Abd Elghani</surname> <given-names>F.</given-names></name> <etal/></person-group>. (<year>2017</year>). <article-title>SUMOylation and ubiquitination reciprocally regulate &#x003B1;-synuclein degradation and pathological aggregation</article-title>. <source>Proc. Natl. Acad. Sci. U S A</source> <volume>114</volume>, <fpage>13176</fpage>&#x02013;<lpage>13181</lpage>. <pub-id pub-id-type="doi">10.1073/pnas.1704351114</pub-id><pub-id pub-id-type="pmid">29180403</pub-id></citation></ref>
<ref id="B225"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Sampson</surname> <given-names>T. R.</given-names></name> <name><surname>Challis</surname> <given-names>C.</given-names></name> <name><surname>Jain</surname> <given-names>N.</given-names></name> <name><surname>Moiseyenko</surname> <given-names>A.</given-names></name> <name><surname>Ladinsky</surname> <given-names>M. S.</given-names></name> <name><surname>Shastri</surname> <given-names>G. G.</given-names></name> <etal/></person-group>. (<year>2020</year>). <article-title>A gut bacterial amyloid promotes &#x003B1;-synuclein aggregation and motor impairment in mice</article-title>. <source>eLife</source> <volume>9</volume>:<fpage>e53111</fpage>. <pub-id pub-id-type="doi">10.7554/eLife.53111</pub-id><pub-id pub-id-type="pmid">32043464</pub-id></citation></ref>
<ref id="B226"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Sampson</surname> <given-names>T. R.</given-names></name> <name><surname>Debelius</surname> <given-names>J. W.</given-names></name> <name><surname>Thron</surname> <given-names>T.</given-names></name> <name><surname>Janssen</surname> <given-names>S.</given-names></name> <name><surname>Shastri</surname> <given-names>G. G.</given-names></name> <name><surname>Ilhan</surname> <given-names>Z. E.</given-names></name> <etal/></person-group>. (<year>2016</year>). <article-title>Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson&#x02019;s disease</article-title>. <source>Cell</source> <volume>167</volume>, <fpage>1469.e12</fpage>&#x02013;<lpage>1480.e12</lpage>. <pub-id pub-id-type="doi">10.1016/j.cell.2016.11.018</pub-id><pub-id pub-id-type="pmid">27912057</pub-id></citation></ref>
<ref id="B227"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Sarkar</surname> <given-names>S.</given-names></name> <name><surname>Dammer</surname> <given-names>E. B.</given-names></name> <name><surname>Malovic</surname> <given-names>E.</given-names></name> <name><surname>Olsen</surname> <given-names>A. L.</given-names></name> <name><surname>Raza</surname> <given-names>S. A.</given-names></name> <name><surname>Gao</surname> <given-names>T.</given-names></name> <etal/></person-group>. (<year>2020</year>). <article-title>Molecular signatures of neuroinflammation induced by &#x003B1;-synuclein aggregates in microglial cells</article-title>. <source>Front. Immunol.</source> <volume>11</volume>:<fpage>33</fpage>. <pub-id pub-id-type="doi">10.3389/fimmu.2020.00033</pub-id><pub-id pub-id-type="pmid">32082315</pub-id></citation></ref>
<ref id="B228"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Schafferer</surname> <given-names>S.</given-names></name> <name><surname>Khurana</surname> <given-names>R.</given-names></name> <name><surname>Refolo</surname> <given-names>V.</given-names></name> <name><surname>Venezia</surname> <given-names>S.</given-names></name> <name><surname>Sturm</surname> <given-names>E.</given-names></name> <name><surname>Piatti</surname> <given-names>P.</given-names></name> <etal/></person-group>. (<year>2016</year>). <article-title>Changes in the miRNA-mRNA regulatory network precede motor symptoms in a mouse model of multiple system atrophy: clinical implications</article-title>. <source>PLoS One</source> <volume>11</volume>:<fpage>e0150705</fpage>. <pub-id pub-id-type="doi">10.1371/journal.pone.0150705</pub-id><pub-id pub-id-type="pmid">26962858</pub-id></citation></ref>
<ref id="B229"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Schaser</surname> <given-names>A. J.</given-names></name> <name><surname>Osterberg</surname> <given-names>V. R.</given-names></name> <name><surname>Dent</surname> <given-names>S. E.</given-names></name> <name><surname>Stackhouse</surname> <given-names>T. L.</given-names></name> <name><surname>Wakeham</surname> <given-names>C. M.</given-names></name> <name><surname>Boutros</surname> <given-names>S. W.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>&#x003B1;-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders</article-title>. <source>Sci. Rep.</source> <volume>9</volume>:<fpage>10919</fpage>. <pub-id pub-id-type="doi">10.1038/s41598-019-47227-z</pub-id><pub-id pub-id-type="pmid">31358782</pub-id></citation></ref>
<ref id="B230"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Schweighauser</surname> <given-names>M.</given-names></name> <name><surname>Bacioglu</surname> <given-names>M.</given-names></name> <name><surname>Fritschi</surname> <given-names>S. K.</given-names></name> <name><surname>Shimshek</surname> <given-names>D. R.</given-names></name> <name><surname>Kahle</surname> <given-names>P. J.</given-names></name> <name><surname>Eisele</surname> <given-names>Y. S.</given-names></name> <etal/></person-group>. (<year>2015</year>). <article-title>Formaldehyde-fixed brain tissue from spontaneously ill &#x003B1;-synuclein transgenic mice induces fatal alpha-synucleinopathy in transgenic hosts</article-title>. <source>Acta Neuropathol.</source> <volume>129</volume>, <fpage>157</fpage>&#x02013;<lpage>159</lpage>. <pub-id pub-id-type="doi">10.1007/s00401-014-1360-5</pub-id><pub-id pub-id-type="pmid">25367384</pub-id></citation></ref>
<ref id="B231"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Schweighauser</surname> <given-names>M.</given-names></name> <name><surname>Shi</surname> <given-names>Y.</given-names></name> <name><surname>Tarutani</surname> <given-names>A.</given-names></name> <name><surname>Kametani</surname> <given-names>F.</given-names></name> <name><surname>Murzin</surname> <given-names>A. G.</given-names></name> <name><surname>Ghetti</surname> <given-names>B.</given-names></name> <etal/></person-group>. (<year>2020</year>). <article-title>Structures of &#x003B1;-synuclein filaments from multiple system atrophy</article-title>. <source>Nature</source> [Epub ahead of print]. <pub-id pub-id-type="doi">10.1038/s41586-020-2317-6</pub-id><pub-id pub-id-type="pmid">32461689</pub-id></citation></ref>
<ref id="B232"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Shahmoradian</surname> <given-names>S. H.</given-names></name> <name><surname>Lewis</surname> <given-names>A. J.</given-names></name> <name><surname>Genoud</surname> <given-names>C.</given-names></name> <name><surname>Hench</surname> <given-names>J.</given-names></name> <name><surname>Moors</surname> <given-names>T. E.</given-names></name> <name><surname>Navarro</surname> <given-names>P. P.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>Lewy pathology in Parkinson&#x02019;s disease consists of crowded organelles and lipid membranes</article-title>. <source>Nat. Neurosci.</source> <volume>22</volume>, <fpage>1099</fpage>&#x02013;<lpage>1109</lpage>. <pub-id pub-id-type="doi">10.1038/s41593-019-0423-2</pub-id><pub-id pub-id-type="pmid">31235907</pub-id></citation></ref>
<ref id="B233"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Shahnawaz</surname> <given-names>M.</given-names></name> <name><surname>Mukherjee</surname> <given-names>A.</given-names></name> <name><surname>Pritzkow</surname> <given-names>S.</given-names></name> <name><surname>Mendez</surname> <given-names>N.</given-names></name> <name><surname>Rabadia</surname> <given-names>P.</given-names></name> <name><surname>Liu</surname> <given-names>X.</given-names></name> <etal/></person-group>. (<year>2020</year>). <article-title>Discriminating &#x003B1;-synuclein strains in Parkinson&#x02019;s disease and multiple system atrophy</article-title>. <source>Nature</source> <volume>578</volume>, <fpage>273</fpage>&#x02013;<lpage>277</lpage>. <pub-id pub-id-type="doi">10.1038/s41586-020-1984-7</pub-id><pub-id pub-id-type="pmid">32025029</pub-id></citation></ref>
<ref id="B234"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Shannon</surname> <given-names>K. M.</given-names></name> <name><surname>Keshavarzian</surname> <given-names>A.</given-names></name> <name><surname>Mutlu</surname> <given-names>E.</given-names></name> <name><surname>Dodiya</surname> <given-names>H. B.</given-names></name> <name><surname>Daian</surname> <given-names>D.</given-names></name> <name><surname>Jaglin</surname> <given-names>J. A.</given-names></name> <etal/></person-group>. (<year>2012</year>). <article-title>&#x003B1;-synuclein in colonic submucosa in early untreated Parkinson&#x02019;s disease</article-title>. <source>Mov. Disord.</source> <volume>27</volume>, <fpage>709</fpage>&#x02013;<lpage>715</lpage>. <pub-id pub-id-type="doi">10.3410/f.717698045.793456802</pub-id><pub-id pub-id-type="pmid">21766334</pub-id></citation></ref>
<ref id="B235"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Shrivastava</surname> <given-names>A. N.</given-names></name> <name><surname>Bousset</surname> <given-names>L.</given-names></name> <name><surname>Renner</surname> <given-names>M.</given-names></name> <name><surname>Redeker</surname> <given-names>V.</given-names></name> <name><surname>Savistchenko</surname> <given-names>J.</given-names></name> <name><surname>Triller</surname> <given-names>A.</given-names></name> <etal/></person-group>. (<year>2020</year>). <article-title>Differential membrane binding and seeding of distinct &#x003B1;-synuclein fibrillar polymorphs</article-title>. <source>Biophys. J.</source> <volume>118</volume>, <fpage>1301</fpage>&#x02013;<lpage>1320</lpage>. <pub-id pub-id-type="doi">10.1016/j.bpj.2020.01.022</pub-id><pub-id pub-id-type="pmid">32059758</pub-id></citation></ref>
<ref id="B236"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Shrivastava</surname> <given-names>A. N.</given-names></name> <name><surname>Redeker</surname> <given-names>V.</given-names></name> <name><surname>Fritz</surname> <given-names>N.</given-names></name> <name><surname>Pieri</surname> <given-names>L.</given-names></name> <name><surname>Almeida</surname> <given-names>L. G.</given-names></name> <name><surname>Spolidoro</surname> <given-names>M.</given-names></name> <etal/></person-group>. (<year>2015</year>). <article-title>&#x003B1;-synuclein assemblies sequester neuronal &#x003B1;3-Na<sup>+</sup>/K<sup>+</sup>-ATPase and impair Na+ gradient</article-title>. <source>EMBO J.</source> <volume>34</volume>, <fpage>2408</fpage>&#x02013;<lpage>2423</lpage>. <pub-id pub-id-type="doi">10.15252/embj.201591397</pub-id><pub-id pub-id-type="pmid">26323479</pub-id></citation></ref>
<ref id="B237"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Sian-Hulsmann</surname> <given-names>J.</given-names></name> <name><surname>Monoranu</surname> <given-names>C.</given-names></name> <name><surname>Strobel</surname> <given-names>S.</given-names></name> <name><surname>Riederer</surname> <given-names>P.</given-names></name></person-group> (<year>2015</year>). <article-title>Lewy bodies: a spectator or salient killer?</article-title> <source>CNS Neurol. Disord. Drug Targets</source> <volume>14</volume>, <fpage>947</fpage>&#x02013;<lpage>955</lpage>. <pub-id pub-id-type="doi">10.2174/1871527314666150317225659</pub-id><pub-id pub-id-type="pmid">31758317</pub-id></citation></ref>
<ref id="B238"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Sidhu</surname> <given-names>A.</given-names></name> <name><surname>Wersinger</surname> <given-names>C.</given-names></name> <name><surname>Vernier</surname> <given-names>P.</given-names></name></person-group> (<year>2004</year>). <article-title>Does &#x003B1;-synuclein modulate dopaminergic synaptic content and tone at the synapse?</article-title> <source>FASEB J.</source> <volume>18</volume>, <fpage>637</fpage>&#x02013;<lpage>647</lpage>. <pub-id pub-id-type="doi">10.1096/fj.03-1112rev</pub-id><pub-id pub-id-type="pmid">15054086</pub-id></citation></ref>
<ref id="B239"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Singleton</surname> <given-names>A. B.</given-names></name> <name><surname>Farrer</surname> <given-names>M.</given-names></name> <name><surname>Johnson</surname> <given-names>J.</given-names></name> <name><surname>Singleton</surname> <given-names>A.</given-names></name> <name><surname>Hague</surname> <given-names>S.</given-names></name> <name><surname>Kachergus</surname> <given-names>J.</given-names></name> <etal/></person-group>. (<year>2003</year>). <article-title>&#x003B1;-Synuclein locus triplication causes Parkinson&#x02019;s disease</article-title>. <source>Science</source> <volume>302</volume>:<fpage>841</fpage>. <pub-id pub-id-type="doi">10.1126/science.1090278</pub-id><pub-id pub-id-type="pmid">14593171</pub-id></citation></ref>
<ref id="B240"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Smith</surname> <given-names>W. W.</given-names></name> <name><surname>Jiang</surname> <given-names>H.</given-names></name> <name><surname>Pei</surname> <given-names>Z.</given-names></name> <name><surname>Tanaka</surname> <given-names>Y.</given-names></name> <name><surname>Morita</surname> <given-names>H.</given-names></name> <name><surname>Sawa</surname> <given-names>A.</given-names></name> <etal/></person-group>. (<year>2005</year>). <article-title>Endoplasmic reticulum stress and mitochondrial cell death pathways mediate A53T mutant &#x003B1;-synuclein-induced toxicity</article-title>. <source>Hum. Mol. Genet.</source> <volume>14</volume>, <fpage>3801</fpage>&#x02013;<lpage>3811</lpage>. <pub-id pub-id-type="doi">10.1093/hmg/ddi396</pub-id><pub-id pub-id-type="pmid">16239241</pub-id></citation></ref>
<ref id="B241"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Snyder</surname> <given-names>H.</given-names></name> <name><surname>Mensah</surname> <given-names>K.</given-names></name> <name><surname>Theisler</surname> <given-names>C.</given-names></name> <name><surname>Lee</surname> <given-names>J.</given-names></name> <name><surname>Matouschek</surname> <given-names>A.</given-names></name> <name><surname>Wolozin</surname> <given-names>B.</given-names></name></person-group> (<year>2003</year>). <article-title>Aggregated and monomeric &#x003B1;-synuclein bind to the S6&#x02019; proteasomal protein and inhibit proteasomal function</article-title>. <source>J. Biol. Chem.</source> <volume>278</volume>, <fpage>11753</fpage>&#x02013;<lpage>11759</lpage>. <pub-id pub-id-type="doi">10.1074/jbc.m208641200</pub-id><pub-id pub-id-type="pmid">12551928</pub-id></citation></ref>
<ref id="B242"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Sommer</surname> <given-names>A.</given-names></name> <name><surname>Marxreiter</surname> <given-names>F.</given-names></name> <name><surname>Krach</surname> <given-names>F.</given-names></name> <name><surname>Fadler</surname> <given-names>T.</given-names></name> <name><surname>Grosch</surname> <given-names>J.</given-names></name> <name><surname>Maroni</surname> <given-names>M.</given-names></name> <etal/></person-group>. (<year>2018</year>). <article-title>Th17 lymphocytes induce neuronal cell death in a human iPSC-based model of Parkinson&#x02019;s disease</article-title>. <source>Cell Stem Cell</source> <volume>23</volume>, <fpage>123.e6</fpage>&#x02013;<lpage>131.e6</lpage>. <pub-id pub-id-type="doi">10.1016/j.stem.2018.06.015</pub-id><pub-id pub-id-type="pmid">29979986</pub-id></citation></ref>
<ref id="B243"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Song</surname> <given-names>Y. J.</given-names></name> <name><surname>Halliday</surname> <given-names>G. M.</given-names></name> <name><surname>Holton</surname> <given-names>J. L.</given-names></name> <name><surname>Lashley</surname> <given-names>T.</given-names></name> <name><surname>O&#x02019;sullivan</surname> <given-names>S. S.</given-names></name> <name><surname>Mccann</surname> <given-names>H.</given-names></name> <etal/></person-group>. (<year>2009</year>). <article-title>Degeneration in different parkinsonian syndromes relates to astrocyte type and astrocyte protein expression</article-title>. <source>J. Neuropathol. Exp. Neurol.</source> <volume>68</volume>, <fpage>1073</fpage>&#x02013;<lpage>1083</lpage>. <pub-id pub-id-type="doi">10.1097/nen.0b013e3181b66f1b</pub-id><pub-id pub-id-type="pmid">19918119</pub-id></citation></ref>
<ref id="B244"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Song</surname> <given-names>Y. J.</given-names></name> <name><surname>Lundvig</surname> <given-names>D. M.</given-names></name> <name><surname>Huang</surname> <given-names>Y.</given-names></name> <name><surname>Gai</surname> <given-names>W. P.</given-names></name> <name><surname>Blumbergs</surname> <given-names>P. C.</given-names></name> <name><surname>Hojrup</surname> <given-names>P.</given-names></name> <etal/></person-group>. (<year>2007</year>). <article-title>p25&#x003B1; relocalizes in oligodendroglia from myelin to cytoplasmic inclusions in multiple system atrophy</article-title>. <source>Am. J. Pathol.</source> <volume>171</volume>, <fpage>1291</fpage>&#x02013;<lpage>1303</lpage>. <pub-id pub-id-type="doi">10.1016/s1353-8020(08)70483-8</pub-id><pub-id pub-id-type="pmid">17823288</pub-id></citation></ref>
<ref id="B245"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Sorrentino</surname> <given-names>Z. A.</given-names></name> <name><surname>Giasson</surname> <given-names>B. I.</given-names></name> <name><surname>Chakrabarty</surname> <given-names>P.</given-names></name></person-group> (<year>2019</year>). <article-title>&#x003B1;-Synuclein and astrocytes: tracing the pathways from homeostasis to neurodegeneration in Lewy body disease</article-title>. <source>Acta Neuropathol.</source> <volume>138</volume>, <fpage>1</fpage>&#x02013;<lpage>21</lpage>. <pub-id pub-id-type="doi">10.1007/s00401-019-01977-2</pub-id><pub-id pub-id-type="pmid">30798354</pub-id></citation></ref>
<ref id="B246"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Spillantini</surname> <given-names>M. G.</given-names></name> <name><surname>Crowther</surname> <given-names>R. A.</given-names></name> <name><surname>Jakes</surname> <given-names>R.</given-names></name> <name><surname>Hasegawa</surname> <given-names>M.</given-names></name> <name><surname>Goedert</surname> <given-names>M.</given-names></name></person-group> (<year>1998</year>). <article-title>&#x003B1;-Synuclein in filamentous inclusions of Lewy bodies from Parkinson&#x02019;s disease and dementia with Lewy bodies</article-title>. <source>Proc. Natl. Acad. Sci. U S A</source> <volume>95</volume>, <fpage>6469</fpage>&#x02013;<lpage>6473</lpage>. <pub-id pub-id-type="doi">10.1073/pnas.95.11.6469</pub-id><pub-id pub-id-type="pmid">9600990</pub-id></citation></ref>
<ref id="B247"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Spillantini</surname> <given-names>M. G.</given-names></name> <name><surname>Schmidt</surname> <given-names>M. L.</given-names></name> <name><surname>Lee</surname> <given-names>V. M.</given-names></name> <name><surname>Trojanowski</surname> <given-names>J. Q.</given-names></name> <name><surname>Jakes</surname> <given-names>R.</given-names></name> <name><surname>Goedert</surname> <given-names>M.</given-names></name></person-group> (<year>1997</year>). <article-title>&#x003B1;-synuclein in Lewy bodies</article-title>. <source>Nature</source> <volume>388</volume>, <fpage>839</fpage>&#x02013;<lpage>840</lpage>. <pub-id pub-id-type="doi">10.1038/42166</pub-id><pub-id pub-id-type="pmid">9278044</pub-id></citation></ref>
<ref id="B248"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Stefanis</surname> <given-names>L.</given-names></name> <name><surname>Larsen</surname> <given-names>K. E.</given-names></name> <name><surname>Rideout</surname> <given-names>H. J.</given-names></name> <name><surname>Sulzer</surname> <given-names>D.</given-names></name> <name><surname>Greene</surname> <given-names>L. A.</given-names></name></person-group> (<year>2001</year>). <article-title>Expression of A53T mutant but not wild-type &#x003B1;-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation system, loss of dopamine release and autophagic cell death</article-title>. <source>J. Neurosci.</source> <volume>21</volume>, <fpage>9549</fpage>&#x02013;<lpage>9560</lpage>. <pub-id pub-id-type="doi">10.1523/jneurosci.21-24-09549.2001</pub-id><pub-id pub-id-type="pmid">11739566</pub-id></citation></ref>
<ref id="B249"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Stefanova</surname> <given-names>N.</given-names></name> <name><surname>Reindl</surname> <given-names>M.</given-names></name> <name><surname>Neumann</surname> <given-names>M.</given-names></name> <name><surname>Kahle</surname> <given-names>P. J.</given-names></name> <name><surname>Poewe</surname> <given-names>W.</given-names></name> <name><surname>Wenning</surname> <given-names>G. K.</given-names></name></person-group> (<year>2007</year>). <article-title>Microglial activation mediates neurodegeneration related to oligodendroglial alpha-synucleinopathy: implications for multiple system atrophy</article-title>. <source>Mov. Disord.</source> <volume>22</volume>, <fpage>2196</fpage>&#x02013;<lpage>2203</lpage>. <pub-id pub-id-type="doi">10.1002/mds.21671</pub-id><pub-id pub-id-type="pmid">17853477</pub-id></citation></ref>
<ref id="B250"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Stokholm</surname> <given-names>M. G.</given-names></name> <name><surname>Iranzo</surname> <given-names>A.</given-names></name> <name><surname>Ostergaard</surname> <given-names>K.</given-names></name> <name><surname>Serradell</surname> <given-names>M.</given-names></name> <name><surname>Otto</surname> <given-names>M.</given-names></name> <name><surname>Svendsen</surname> <given-names>K. B.</given-names></name> <etal/></person-group>. (<year>2017</year>). <article-title>Assessment of neuroinflammation in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study</article-title>. <source>Lancet Neurol.</source> <volume>16</volume>, <fpage>789</fpage>&#x02013;<lpage>796</lpage>. <pub-id pub-id-type="doi">10.1016/s1474-4422(17)30173-4</pub-id><pub-id pub-id-type="pmid">28684245</pub-id></citation></ref>
<ref id="B251"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Su</surname> <given-names>X.</given-names></name> <name><surname>Maguire-Zeiss</surname> <given-names>K. A.</given-names></name> <name><surname>Giuliano</surname> <given-names>R.</given-names></name> <name><surname>Prifti</surname> <given-names>L.</given-names></name> <name><surname>Venkatesh</surname> <given-names>K.</given-names></name> <name><surname>Federoff</surname> <given-names>H. J.</given-names></name></person-group> (<year>2008</year>). <article-title>Synuclein activates microglia in a model of Parkinson&#x02019;s disease</article-title>. <source>Neurobiol. Aging</source> <volume>29</volume>, <fpage>1690</fpage>&#x02013;<lpage>1701</lpage>. <pub-id pub-id-type="doi">10.1016/j.neurobiolaging.2007.04.006</pub-id><pub-id pub-id-type="pmid">17537546</pub-id></citation></ref>
<ref id="B252"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Sulzer</surname> <given-names>D.</given-names></name> <name><surname>Alcalay</surname> <given-names>R. N.</given-names></name> <name><surname>Garretti</surname> <given-names>F.</given-names></name> <name><surname>Cote</surname> <given-names>L.</given-names></name> <name><surname>Kanter</surname> <given-names>E.</given-names></name> <name><surname>Agin-Liebes</surname> <given-names>J.</given-names></name> <etal/></person-group>. (<year>2017</year>). <article-title>T cells from patients with Parkinson&#x02019;s disease recognize &#x003B1;-synuclein peptides</article-title>. <source>Nature</source> <volume>546</volume>, <fpage>656</fpage>&#x02013;<lpage>661</lpage>. <pub-id pub-id-type="doi">10.1038/nature22815</pub-id><pub-id pub-id-type="pmid">28636593</pub-id></citation></ref>
<ref id="B253"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Surendranathan</surname> <given-names>A.</given-names></name> <name><surname>Su</surname> <given-names>L.</given-names></name> <name><surname>Mak</surname> <given-names>E.</given-names></name> <name><surname>Passamonti</surname> <given-names>L.</given-names></name> <name><surname>Hong</surname> <given-names>Y. T.</given-names></name> <name><surname>Arnold</surname> <given-names>R.</given-names></name> <etal/></person-group>. (<year>2018</year>). <article-title>Early microglial activation and peripheral inflammation in dementia with Lewy bodies</article-title>. <source>Brain</source> <volume>141</volume>, <fpage>3415</fpage>&#x02013;<lpage>3427</lpage>. <pub-id pub-id-type="doi">10.1093/brain/awy265</pub-id><pub-id pub-id-type="pmid">30403785</pub-id></citation></ref>
<ref id="B254"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Surguchev</surname> <given-names>A. A.</given-names></name> <name><surname>Surguchov</surname> <given-names>A.</given-names></name></person-group> (<year>2017</year>). <article-title>Synucleins and gene expression: ramblers in a crowd or cops regulating traffic?</article-title> <source>Front. Mol. Neurosci.</source> <volume>10</volume>:<fpage>224</fpage>. <pub-id pub-id-type="doi">10.3389/fnmol.2017.00224</pub-id><pub-id pub-id-type="pmid">28751856</pub-id></citation></ref>
<ref id="B255"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Surmeier</surname> <given-names>D. J.</given-names></name> <name><surname>Obeso</surname> <given-names>J. A.</given-names></name> <name><surname>Halliday</surname> <given-names>G. M.</given-names></name></person-group> (<year>2017</year>). <article-title>Parkinson&#x02019;s disease is not simply a prion disorder</article-title>. <source>J. Neurosci.</source> <volume>37</volume>, <fpage>9799</fpage>&#x02013;<lpage>9807</lpage>. <pub-id pub-id-type="doi">10.1523/jneurosci.1787-16.2017</pub-id><pub-id pub-id-type="pmid">29021297</pub-id></citation></ref>
<ref id="B256"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Svensson</surname> <given-names>E.</given-names></name> <name><surname>Horv&#x000E1;th-Puh&#x000F3;</surname> <given-names>E.</given-names></name> <name><surname>Thomsen</surname> <given-names>R. W.</given-names></name> <name><surname>Djurhuus</surname> <given-names>J. C.</given-names></name> <name><surname>Pedersen</surname> <given-names>L.</given-names></name> <name><surname>Borghammer</surname> <given-names>P.</given-names></name> <etal/></person-group>. (<year>2015</year>). <article-title>Vagotomy and subsequent risk of Parkinson&#x02019;s disease</article-title>. <source>Ann. Neurol.</source> <volume>78</volume>, <fpage>522</fpage>&#x02013;<lpage>529</lpage>. <pub-id pub-id-type="doi">10.1002/ana.24448</pub-id><pub-id pub-id-type="pmid">26031848</pub-id></citation></ref>
<ref id="B257"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Tanaka</surname> <given-names>Y.</given-names></name> <name><surname>Engelender</surname> <given-names>S.</given-names></name> <name><surname>Igarashi</surname> <given-names>S.</given-names></name> <name><surname>Rao</surname> <given-names>R. K.</given-names></name> <name><surname>Wanner</surname> <given-names>T.</given-names></name> <name><surname>Tanzi</surname> <given-names>R. E.</given-names></name> <etal/></person-group>. (<year>2001</year>). <article-title>Inducible expression of mutant &#x003B1;-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis</article-title>. <source>Hum. Mol. Genet.</source> <volume>10</volume>, <fpage>919</fpage>&#x02013;<lpage>926</lpage>. <pub-id pub-id-type="doi">10.1093/hmg/10.9.919</pub-id><pub-id pub-id-type="pmid">11309365</pub-id></citation></ref>
<ref id="B258"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Tapias</surname> <given-names>V.</given-names></name> <name><surname>Hu</surname> <given-names>X.</given-names></name> <name><surname>Luk</surname> <given-names>K. C.</given-names></name> <name><surname>Sanders</surname> <given-names>L. H.</given-names></name> <name><surname>Lee</surname> <given-names>V. M.</given-names></name> <name><surname>Greenamyre</surname> <given-names>J. T.</given-names></name></person-group> (<year>2017</year>). <article-title>Synthetic &#x003B1;-synuclein fibrils cause mitochondrial impairment and selective dopamine neurodegeneration in part <italic>via</italic> iNOS-mediated nitric oxide production</article-title>. <source>Cell. Mol. Life Sci.</source> <volume>74</volume>, <fpage>2851</fpage>&#x02013;<lpage>2874</lpage>. <pub-id pub-id-type="doi">10.1007/s00018-017-2541-x</pub-id><pub-id pub-id-type="pmid">28534083</pub-id></citation></ref>
<ref id="B259"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Thaisetthawatkul</surname> <given-names>P.</given-names></name></person-group> (<year>2016</year>). <article-title>Pure autonomic failure</article-title>. <source>Curr. Neurol. Neurosci. Rep.</source> <volume>16</volume>:<fpage>74</fpage>. <pub-id pub-id-type="doi">10.1007/s11910-016-0673-2</pub-id><pub-id pub-id-type="pmid">27338613</pub-id></citation></ref>
<ref id="B260"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Theillet</surname> <given-names>F. X.</given-names></name> <name><surname>Binolfi</surname> <given-names>A.</given-names></name> <name><surname>Bekei</surname> <given-names>B.</given-names></name> <name><surname>Martorana</surname> <given-names>A.</given-names></name> <name><surname>Rose</surname> <given-names>H. M.</given-names></name> <name><surname>Stuiver</surname> <given-names>M.</given-names></name> <etal/></person-group>. (<year>2016</year>). <article-title>Structural disorder of monomeric &#x003B1;-synuclein persists in mammalian cells</article-title>. <source>Nature</source> <volume>530</volume>, <fpage>45</fpage>&#x02013;<lpage>50</lpage>. <pub-id pub-id-type="doi">10.1038/nature16531</pub-id><pub-id pub-id-type="pmid">26808899</pub-id></citation></ref>
<ref id="B261"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Theodore</surname> <given-names>S.</given-names></name> <name><surname>Cao</surname> <given-names>S.</given-names></name> <name><surname>Mclean</surname> <given-names>P. J.</given-names></name> <name><surname>Standaert</surname> <given-names>D. G.</given-names></name></person-group> (<year>2008</year>). <article-title>Targeted overexpression of human &#x003B1;-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease</article-title>. <source>J. Neuropathol. Exp. Neurol.</source> <volume>67</volume>, <fpage>1149</fpage>&#x02013;<lpage>1158</lpage>. <pub-id pub-id-type="doi">10.1097/nen.0b013e31818e5e99</pub-id><pub-id pub-id-type="pmid">19018246</pub-id></citation></ref>
<ref id="B262"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Tolosa</surname> <given-names>E.</given-names></name> <name><surname>Vila</surname> <given-names>M.</given-names></name> <name><surname>Klein</surname> <given-names>C.</given-names></name> <name><surname>Rascol</surname> <given-names>O.</given-names></name></person-group> (<year>2020</year>). <article-title>LRRK2 in Parkinson disease: challenges of clinical trials</article-title>. <source>Nat. Rev. Neurol.</source> <volume>16</volume>, <fpage>97</fpage>&#x02013;<lpage>107</lpage>. <pub-id pub-id-type="doi">10.1038/s41582-019-0301-2</pub-id><pub-id pub-id-type="pmid">31980808</pub-id></citation></ref>
<ref id="B263"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Tosatto</surname> <given-names>L.</given-names></name> <name><surname>Andrighetti</surname> <given-names>A. O.</given-names></name> <name><surname>Plotegher</surname> <given-names>N.</given-names></name> <name><surname>Antonini</surname> <given-names>V.</given-names></name> <name><surname>Tessari</surname> <given-names>I.</given-names></name> <name><surname>Ricci</surname> <given-names>L.</given-names></name> <etal/></person-group>. (<year>2012</year>). <article-title>&#x003B1;-synuclein pore forming activity upon membrane association</article-title>. <source>Biochim. Biophys. Acta</source> <volume>1818</volume>, <fpage>2876</fpage>&#x02013;<lpage>2883</lpage>. <pub-id pub-id-type="doi">10.1016/j.bbamem.2012.07.007</pub-id><pub-id pub-id-type="pmid">22820150</pub-id></citation></ref>
<ref id="B264"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Tozzi</surname> <given-names>A.</given-names></name> <name><surname>De Iure</surname> <given-names>A.</given-names></name> <name><surname>Bagetta</surname> <given-names>V.</given-names></name> <name><surname>Tantucci</surname> <given-names>M.</given-names></name> <name><surname>Durante</surname> <given-names>V.</given-names></name> <name><surname>Quiroga-Varela</surname> <given-names>A.</given-names></name> <etal/></person-group>. (<year>2016</year>). <article-title>&#x003B1;-synuclein produces early behavioral alterations <italic>via</italic> striatal cholinergic synaptic dysfunction by interacting with GluN2D N-methyl-D-aspartate receptor subunit</article-title>. <source>Biol. Psychiatry</source> <volume>79</volume>, <fpage>402</fpage>&#x02013;<lpage>414</lpage>. <pub-id pub-id-type="doi">10.1016/j.biopsych.2015.08.013</pub-id><pub-id pub-id-type="pmid">26392130</pub-id></citation></ref>
<ref id="B265"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Tremblay</surname> <given-names>M. E.</given-names></name> <name><surname>Cookson</surname> <given-names>M. R.</given-names></name> <name><surname>Civiero</surname> <given-names>L.</given-names></name></person-group> (<year>2019</year>). <article-title>Glial phagocytic clearance in Parkinson&#x02019;s disease</article-title>. <source>Mol. Neurodegener.</source> <volume>14</volume>:<fpage>16</fpage>. <pub-id pub-id-type="doi">10.1186/s13024-019-0314-8</pub-id><pub-id pub-id-type="pmid">30953527</pub-id></citation></ref>
<ref id="B266"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Tsigelny</surname> <given-names>I. F.</given-names></name> <name><surname>Sharikov</surname> <given-names>Y.</given-names></name> <name><surname>Wrasidlo</surname> <given-names>W.</given-names></name> <name><surname>Gonzalez</surname> <given-names>T.</given-names></name> <name><surname>Desplats</surname> <given-names>P. A.</given-names></name> <name><surname>Crews</surname> <given-names>L.</given-names></name> <etal/></person-group>. (<year>2012</year>). <article-title>Role of &#x003B1;-synuclein penetration into the membrane in the mechanisms of oligomer pore formation</article-title>. <source>FEBS J.</source> <volume>279</volume>, <fpage>1000</fpage>&#x02013;<lpage>1013</lpage>. <pub-id pub-id-type="doi">10.1111/j.1742-4658.2012.08489.x</pub-id><pub-id pub-id-type="pmid">22251432</pub-id></citation></ref>
<ref id="B267"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Tysnes</surname> <given-names>O. B.</given-names></name> <name><surname>Kenborg</surname> <given-names>L.</given-names></name> <name><surname>Herlofson</surname> <given-names>K.</given-names></name> <name><surname>Steding-Jessen</surname> <given-names>M.</given-names></name> <name><surname>Horn</surname> <given-names>A.</given-names></name> <name><surname>Olsen</surname> <given-names>J. H.</given-names></name> <etal/></person-group>. (<year>2015</year>). <article-title>Does vagotomy reduce the risk of Parkinson&#x02019;s disease?</article-title> <source>Ann. Neurol.</source> <volume>78</volume>, <fpage>1011</fpage>&#x02013;<lpage>1012</lpage>. <pub-id pub-id-type="doi">10.1097/01.nt.0000475926.46736.74</pub-id><pub-id pub-id-type="pmid">26418122</pub-id></citation></ref>
<ref id="B268"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ubhi</surname> <given-names>K.</given-names></name> <name><surname>Rockenstein</surname> <given-names>E.</given-names></name> <name><surname>Mante</surname> <given-names>M.</given-names></name> <name><surname>Patrick</surname> <given-names>C.</given-names></name> <name><surname>Adame</surname> <given-names>A.</given-names></name> <name><surname>Thukral</surname> <given-names>M.</given-names></name> <etal/></person-group>. (<year>2008</year>). <article-title>Rifampicin reduces &#x003B1;-synuclein in a transgenic mouse model of multiple system atrophy</article-title>. <source>Neuroreport</source> <volume>19</volume>, <fpage>1271</fpage>&#x02013;<lpage>1276</lpage>. <pub-id pub-id-type="doi">10.1097/wnr.0b013e32830b3661</pub-id><pub-id pub-id-type="pmid">18695506</pub-id></citation></ref>
<ref id="B269"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ulusoy</surname> <given-names>A.</given-names></name> <name><surname>Rusconi</surname> <given-names>R.</given-names></name> <name><surname>Perez-Revuelta</surname> <given-names>B. I.</given-names></name> <name><surname>Musgrove</surname> <given-names>R. E.</given-names></name> <name><surname>Helwig</surname> <given-names>M.</given-names></name> <name><surname>Winzen-Reichert</surname> <given-names>B.</given-names></name> <etal/></person-group>. (<year>2013</year>). <article-title>Caudo-rostral brain spreading of &#x003B1;-synuclein through vagal connections</article-title>. <source>EMBO Mol. Med.</source> <volume>5</volume>, <fpage>1119</fpage>&#x02013;<lpage>1127</lpage>. <pub-id pub-id-type="doi">10.1002/emmm.201302475</pub-id><pub-id pub-id-type="pmid">23703938</pub-id></citation></ref>
<ref id="B270"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Uversky</surname> <given-names>V. N.</given-names></name> <name><surname>Li</surname> <given-names>J.</given-names></name> <name><surname>Fink</surname> <given-names>A. L.</given-names></name></person-group> (<year>2001</year>). <article-title>Metal-triggered structural transformations, aggregation and fibrillation of human &#x003B1;-synuclein. A possible molecular NK between Parkinson&#x02019;s disease and heavy metal exposure</article-title>. <source>J. Biol. Chem.</source> <volume>276</volume>, <fpage>44284</fpage>&#x02013;<lpage>44296</lpage>. <pub-id pub-id-type="doi">10.1074/jbc.m105343200</pub-id><pub-id pub-id-type="pmid">11553618</pub-id></citation></ref>
<ref id="B271"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Van Der Perren</surname> <given-names>A.</given-names></name> <name><surname>Gelders</surname> <given-names>G.</given-names></name> <name><surname>Fenyi</surname> <given-names>A.</given-names></name> <name><surname>Bousset</surname> <given-names>L.</given-names></name> <name><surname>Brito</surname> <given-names>F.</given-names></name> <name><surname>Peelaerts</surname> <given-names>W.</given-names></name> <etal/></person-group>. (<year>2020</year>). <article-title>The structural differences between patient-derived &#x003B1;-synuclein strains dictate characteristics of Parkinson&#x02019;s disease, multiple system atrophy and dementia with Lewy bodies</article-title>. <source>Acta Neuropathol.</source> <volume>139</volume>, <fpage>977</fpage>&#x02013;<lpage>1000</lpage>. <pub-id pub-id-type="doi">10.1007/s00401-020-02157-3</pub-id><pub-id pub-id-type="pmid">32356200</pub-id></citation></ref>
<ref id="B272"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Varkey</surname> <given-names>J.</given-names></name> <name><surname>Isas</surname> <given-names>J. M.</given-names></name> <name><surname>Mizuno</surname> <given-names>N.</given-names></name> <name><surname>Jensen</surname> <given-names>M. B.</given-names></name> <name><surname>Bhatia</surname> <given-names>V. K.</given-names></name> <name><surname>Jao</surname> <given-names>C. C.</given-names></name> <etal/></person-group>. (<year>2010</year>). <article-title>Membrane curvature induction and tubulation are common features of synucleins and apolipoproteins</article-title>. <source>J. Biol. Chem.</source> <volume>285</volume>, <fpage>32486</fpage>&#x02013;<lpage>32493</lpage>. <pub-id pub-id-type="doi">10.1074/jbc.m110.139576</pub-id><pub-id pub-id-type="pmid">20693280</pub-id></citation></ref>
<ref id="B273"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Vasquez</surname> <given-names>V.</given-names></name> <name><surname>Mitra</surname> <given-names>J.</given-names></name> <name><surname>Hegde</surname> <given-names>P. M.</given-names></name> <name><surname>Pandey</surname> <given-names>A.</given-names></name> <name><surname>Sengupta</surname> <given-names>S.</given-names></name> <name><surname>Mitra</surname> <given-names>S.</given-names></name> <etal/></person-group>. (<year>2017</year>). <article-title>Chromatin-bound oxidized &#x003B1;-synuclein causes strand breaks in neuronal genomes in in vitro models of Parkinson&#x02019;s disease</article-title>. <source>J. Alzheimers Dis.</source> <volume>60</volume>, <fpage>S133</fpage>&#x02013;<lpage>S150</lpage>. <pub-id pub-id-type="doi">10.3233/jad-170342</pub-id><pub-id pub-id-type="pmid">28731447</pub-id></citation></ref>
<ref id="B274"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Venezia</surname> <given-names>S.</given-names></name> <name><surname>Refolo</surname> <given-names>V.</given-names></name> <name><surname>Polissidis</surname> <given-names>A.</given-names></name> <name><surname>Stefanis</surname> <given-names>L.</given-names></name> <name><surname>Wenning</surname> <given-names>G. K.</given-names></name> <name><surname>Stefanova</surname> <given-names>N.</given-names></name></person-group> (<year>2017</year>). <article-title>Toll-like receptor 4 stimulation with monophosphoryl lipid A ameliorates motor deficits and nigral neurodegeneration triggered by extraneuronal alpha-synucleinopathy</article-title>. <source>Mol. Neurodegener.</source> <volume>12</volume>:<fpage>52</fpage>. <pub-id pub-id-type="doi">10.1186/s13024-017-0195-7</pub-id><pub-id pub-id-type="pmid">28676095</pub-id></citation></ref>
<ref id="B275"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Vicario</surname> <given-names>M.</given-names></name> <name><surname>Cieri</surname> <given-names>D.</given-names></name> <name><surname>Brini</surname> <given-names>M.</given-names></name> <name><surname>Cali</surname> <given-names>T.</given-names></name></person-group> (<year>2018</year>). <article-title>The close encounter between &#x003B1;-synuclein and mitochondria</article-title>. <source>Front. Neurosci.</source> <volume>12</volume>:<fpage>388</fpage>. <pub-id pub-id-type="doi">10.3389/fnins.2018.00388</pub-id><pub-id pub-id-type="pmid">29930495</pub-id></citation></ref>
<ref id="B276"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Vicente Miranda</surname> <given-names>H.</given-names></name> <name><surname>Cassio</surname> <given-names>R.</given-names></name> <name><surname>Correia-Guedes</surname> <given-names>L.</given-names></name> <name><surname>Gomes</surname> <given-names>M. A.</given-names></name> <name><surname>Chegao</surname> <given-names>A.</given-names></name> <name><surname>Miranda</surname> <given-names>E.</given-names></name> <etal/></person-group>. (<year>2017</year>). <article-title>Posttranslational modifications of blood-derived &#x003B1;-synuclein as biochemical markers for Parkinson&#x02019;s disease</article-title>. <source>Sci. Rep.</source> <volume>7</volume>:<fpage>13713</fpage>. <pub-id pub-id-type="doi">10.1038/s41598-017-14175-5</pub-id><pub-id pub-id-type="pmid">29057912</pub-id></citation></ref>
<ref id="B277"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Volpicelli-Daley</surname> <given-names>L. A.</given-names></name></person-group> (<year>2017</year>). <article-title>Effects of &#x003B1;-synuclein on axonal transport</article-title>. <source>Neurobiol. Dis.</source> <volume>105</volume>, <fpage>321</fpage>&#x02013;<lpage>327</lpage>. <pub-id pub-id-type="doi">10.1016/j.nbd.2016.12.008</pub-id><pub-id pub-id-type="pmid">27956085</pub-id></citation></ref>
<ref id="B278"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Volpicelli-Daley</surname> <given-names>L. A.</given-names></name> <name><surname>Luk</surname> <given-names>K. C.</given-names></name> <name><surname>Patel</surname> <given-names>T. P.</given-names></name> <name><surname>Tanik</surname> <given-names>S. A.</given-names></name> <name><surname>Riddle</surname> <given-names>D. M.</given-names></name> <name><surname>Stieber</surname> <given-names>A.</given-names></name> <etal/></person-group>. (<year>2011</year>). <article-title>Exogenous &#x003B1;-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death</article-title>. <source>Neuron</source> <volume>72</volume>, <fpage>57</fpage>&#x02013;<lpage>71</lpage>. <pub-id pub-id-type="doi">10.1016/j.neuron.2011.08.033</pub-id><pub-id pub-id-type="pmid">21982369</pub-id></citation></ref>
<ref id="B279"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname> <given-names>W.</given-names></name> <name><surname>Nguyen</surname> <given-names>L. T.</given-names></name> <name><surname>Burlak</surname> <given-names>C.</given-names></name> <name><surname>Chegini</surname> <given-names>F.</given-names></name> <name><surname>Guo</surname> <given-names>F.</given-names></name> <name><surname>Chataway</surname> <given-names>T.</given-names></name> <etal/></person-group>. (<year>2016</year>). <article-title>Caspase-1 causes truncation and aggregation of the Parkinson&#x02019;s disease-associated protein &#x003B1;-synuclein</article-title>. <source>Proc. Natl. Acad. Sci. U S A</source> <volume>113</volume>, <fpage>9587</fpage>&#x02013;<lpage>9592</lpage>. <pub-id pub-id-type="doi">10.1073/pnas.1610099113</pub-id><pub-id pub-id-type="pmid">27482083</pub-id></citation></ref>
<ref id="B280"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname> <given-names>W.</given-names></name> <name><surname>Perovic</surname> <given-names>I.</given-names></name> <name><surname>Chittuluru</surname> <given-names>J.</given-names></name> <name><surname>Kaganovich</surname> <given-names>A.</given-names></name> <name><surname>Nguyen</surname> <given-names>L. T.</given-names></name> <name><surname>Liao</surname> <given-names>J.</given-names></name> <etal/></person-group>. (<year>2011</year>). <article-title>A soluble &#x003B1;-synuclein construct forms a dynamic tetramer</article-title>. <source>Proc. Natl. Acad. Sci. U S A</source> <volume>108</volume>, <fpage>17797</fpage>&#x02013;<lpage>17802</lpage>. <pub-id pub-id-type="doi">10.1073/pnas.1113260108</pub-id><pub-id pub-id-type="pmid">22006323</pub-id></citation></ref>
<ref id="B281"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname> <given-names>X.</given-names></name> <name><surname>Becker</surname> <given-names>K.</given-names></name> <name><surname>Levine</surname> <given-names>N.</given-names></name> <name><surname>Zhang</surname> <given-names>M.</given-names></name> <name><surname>Lieberman</surname> <given-names>A. P.</given-names></name> <name><surname>Moore</surname> <given-names>D. J.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>Pathogenic &#x003B1;-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration</article-title>. <source>Acta Neuropathol. Commun.</source> <volume>7</volume>:<fpage>41</fpage>. <pub-id pub-id-type="doi">10.1186/s40478-019-0696-4</pub-id><pub-id pub-id-type="pmid">30871620</pub-id></citation></ref>
<ref id="B282"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname> <given-names>X. J.</given-names></name> <name><surname>Ma</surname> <given-names>M. M.</given-names></name> <name><surname>Zhou</surname> <given-names>L. B.</given-names></name> <name><surname>Jiang</surname> <given-names>X. Y.</given-names></name> <name><surname>Hao</surname> <given-names>M. M.</given-names></name> <name><surname>Teng</surname> <given-names>R. K. F.</given-names></name> <etal/></person-group>. (<year>2020</year>). <article-title>Autonomic ganglionic injection of &#x003B1;-synuclein fibrils as a model of pure autonomic failure alpha-synucleinopathy</article-title>. <source>Nat. Commun.</source> <volume>11</volume>:<fpage>934</fpage>. <pub-id pub-id-type="doi">10.1038/s41467-019-14189-9</pub-id><pub-id pub-id-type="pmid">32071315</pub-id></citation></ref>
<ref id="B283"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Watts</surname> <given-names>J. C.</given-names></name></person-group> (<year>2019</year>). <article-title>Calling &#x003B1;-synuclein a prion is scientifically justifiable</article-title>. <source>Acta Neuropathol.</source> <volume>138</volume>, <fpage>505</fpage>&#x02013;<lpage>508</lpage>. <pub-id pub-id-type="doi">10.1007/s00401-019-02058-0</pub-id><pub-id pub-id-type="pmid">31407029</pub-id></citation></ref>
<ref id="B284"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wegrzynowicz</surname> <given-names>M.</given-names></name> <name><surname>Bar-On</surname> <given-names>D.</given-names></name> <name><surname>Calo</surname> <given-names>L.</given-names></name> <name><surname>Anichtchik</surname> <given-names>O.</given-names></name> <name><surname>Iovino</surname> <given-names>M.</given-names></name> <name><surname>Xia</surname> <given-names>J.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>Depopulation of dense &#x003B1;-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson&#x02019;s disease model</article-title>. <source>Acta Neuropathol.</source> <volume>138</volume>, <fpage>575</fpage>&#x02013;<lpage>595</lpage>. <pub-id pub-id-type="doi">10.1007/s00401-019-02023-x</pub-id><pub-id pub-id-type="pmid">31165254</pub-id></citation></ref>
<ref id="B285"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wenning</surname> <given-names>G.</given-names></name> <name><surname>Trojanowski</surname> <given-names>J. Q.</given-names></name> <name><surname>Kaufmann</surname> <given-names>H.</given-names></name> <name><surname>Wisniewski</surname> <given-names>T.</given-names></name> <name><surname>Rocca</surname> <given-names>W. A.</given-names></name> <name><surname>Low</surname> <given-names>P. A.</given-names></name></person-group> (<year>2018</year>). <article-title>Is multiple system atrophy an infectious disease?</article-title> <source>Ann. Neurol.</source> <volume>83</volume>, <fpage>10</fpage>&#x02013;<lpage>12</lpage>. <pub-id pub-id-type="doi">10.1002/ana.25132</pub-id><pub-id pub-id-type="pmid">29293269</pub-id></citation></ref>
<ref id="B286"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Woerman</surname> <given-names>A. L.</given-names></name> <name><surname>Kazmi</surname> <given-names>S. A.</given-names></name> <name><surname>Patel</surname> <given-names>S.</given-names></name> <name><surname>Freyman</surname> <given-names>Y.</given-names></name> <name><surname>Oehler</surname> <given-names>A.</given-names></name> <name><surname>Aoyagi</surname> <given-names>A.</given-names></name> <etal/></person-group>. (<year>2018</year>). <article-title>MSA prions exhibit remarkable stability and resistance to inactivation</article-title>. <source>Acta Neuropathol.</source> <volume>135</volume>, <fpage>49</fpage>&#x02013;<lpage>63</lpage>. <pub-id pub-id-type="doi">10.1007/s00401-017-1762-2</pub-id><pub-id pub-id-type="pmid">28849371</pub-id></citation></ref>
<ref id="B287"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wu</surname> <given-names>Q.</given-names></name> <name><surname>Takano</surname> <given-names>H.</given-names></name> <name><surname>Riddle</surname> <given-names>D. M.</given-names></name> <name><surname>Trojanowski</surname> <given-names>J. Q.</given-names></name> <name><surname>Coulter</surname> <given-names>D. A.</given-names></name> <name><surname>Lee</surname> <given-names>V. M.</given-names></name></person-group> (<year>2019</year>). <article-title>&#x003B1;-synuclein (&#x003B1;Syn) preformed fibrils induce endogenous alphasyn aggregation, compromise synaptic activity and enhance synapse loss in cultured excitatory hippocampal neurons</article-title>. <source>J. Neurosci.</source> <volume>39</volume>, <fpage>5080</fpage>&#x02013;<lpage>5094</lpage>. <pub-id pub-id-type="doi">10.1523/jneurosci.0060-19.2019</pub-id><pub-id pub-id-type="pmid">31036761</pub-id></citation></ref>
<ref id="B288"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Yamasaki</surname> <given-names>T. R.</given-names></name> <name><surname>Holmes</surname> <given-names>B. B.</given-names></name> <name><surname>Furman</surname> <given-names>J. L.</given-names></name> <name><surname>Dhavale</surname> <given-names>D. D.</given-names></name> <name><surname>Su</surname> <given-names>B. W.</given-names></name> <name><surname>Song</surname> <given-names>E. S.</given-names></name> <etal/></person-group>. (<year>2019</year>). <article-title>Parkinson&#x02019;s disease and multiple system atrophy have distinct &#x003B1;-synuclein seed characteristics</article-title>. <source>J. Biol. Chem.</source> <volume>294</volume>, <fpage>1045</fpage>&#x02013;<lpage>1058</lpage>. <pub-id pub-id-type="doi">10.1074/jbc.RA118.004471</pub-id><pub-id pub-id-type="pmid">30478174</pub-id></citation></ref>
<ref id="B289"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Yu</surname> <given-names>S.</given-names></name> <name><surname>U&#x000E9;da</surname> <given-names>K.</given-names></name> <name><surname>Chan</surname> <given-names>P.</given-names></name></person-group> (<year>2005</year>). <article-title>&#x003B1;-synuclein and dopamine metabolism</article-title>. <source>Mol. Neurobiol.</source> <volume>31</volume>, <fpage>243</fpage>&#x02013;<lpage>254</lpage>. <pub-id pub-id-type="doi">10.1385/MN:31:1-3:243</pub-id><pub-id pub-id-type="pmid">15953825</pub-id></citation></ref>
<ref id="B290"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Zafar</surname> <given-names>F.</given-names></name> <name><surname>Valappil</surname> <given-names>R. A.</given-names></name> <name><surname>Kim</surname> <given-names>S.</given-names></name> <name><surname>Johansen</surname> <given-names>K. K.</given-names></name> <name><surname>Chang</surname> <given-names>A. L. S.</given-names></name> <name><surname>Tetrud</surname> <given-names>J. W.</given-names></name> <etal/></person-group>. (<year>2018</year>). <article-title>Genetic fine-mapping of the Iowan <italic>SNCA</italic> gene triplication in a patient with Parkinson&#x02019;s disease</article-title>. <source>NPJ Parkinsons Dis.</source> <volume>4</volume>:<fpage>18</fpage>. <pub-id pub-id-type="doi">10.1038/s41531-018-0054-4</pub-id><pub-id pub-id-type="pmid">29928688</pub-id></citation></ref>
<ref id="B291"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Zhang</surname> <given-names>J.</given-names></name> <name><surname>Li</surname> <given-names>X.</given-names></name> <name><surname>Li</surname> <given-names>J. D.</given-names></name></person-group> (<year>2019</year>). <article-title>The roles of post-translational modifications on &#x003B1;-synuclein in the pathogenesis of Parkinson&#x02019;s diseases</article-title>. <source>Front. Neurosci.</source> <volume>13</volume>:<fpage>381</fpage>. <pub-id pub-id-type="doi">10.3389/fnins.2019.00381</pub-id><pub-id pub-id-type="pmid">31057362</pub-id></citation></ref>
<ref id="B292"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Zhang</surname> <given-names>W.</given-names></name> <name><surname>Wang</surname> <given-names>T.</given-names></name> <name><surname>Pei</surname> <given-names>Z.</given-names></name> <name><surname>Miller</surname> <given-names>D. S.</given-names></name> <name><surname>Wu</surname> <given-names>X.</given-names></name> <name><surname>Block</surname> <given-names>M. L.</given-names></name> <etal/></person-group>. (<year>2005</year>). <article-title>Aggregated &#x003B1;-synuclein activates microglia: a process leading to disease progression in Parkinson&#x02019;s disease</article-title>. <source>FASEB J.</source> <volume>19</volume>, <fpage>533</fpage>&#x02013;<lpage>542</lpage>. <pub-id pub-id-type="doi">10.1096/fj.04-2751com</pub-id><pub-id pub-id-type="pmid">15791003</pub-id></citation></ref>
<ref id="B293"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Zhao</surname> <given-names>H. T.</given-names></name> <name><surname>John</surname> <given-names>N.</given-names></name> <name><surname>Delic</surname> <given-names>V.</given-names></name> <name><surname>Ikeda-Lee</surname> <given-names>K.</given-names></name> <name><surname>Kim</surname> <given-names>A.</given-names></name> <name><surname>Weihofen</surname> <given-names>A.</given-names></name> <etal/></person-group>. (<year>2017</year>). <article-title>LRRK2 antisense oligonucleotides ameliorate &#x003B1;-synuclein inclusion formation in a Parkinson&#x02019;s disease mouse model</article-title>. <source>Mol. Ther. Nucleic Acids</source> <volume>8</volume>, <fpage>508</fpage>&#x02013;<lpage>519</lpage>. <pub-id pub-id-type="doi">10.1016/j.omtn.2017.08.002</pub-id><pub-id pub-id-type="pmid">28918051</pub-id></citation></ref>
<ref id="B294"><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Zheng</surname> <given-names>B.</given-names></name> <name><surname>Liao</surname> <given-names>Z.</given-names></name> <name><surname>Locascio</surname> <given-names>J. J.</given-names></name> <name><surname>Lesniak</surname> <given-names>K. A.</given-names></name> <name><surname>Roderick</surname> <given-names>S. S.</given-names></name> <name><surname>Watt</surname> <given-names>M. L.</given-names></name> <etal/></person-group>. (<year>2010</year>). <article-title>PGC-1&#x003B1;, a potential therapeutic target for early intervention in Parkinson&#x02019;s disease</article-title>. <source>Sci. Transl. Med.</source> <volume>2</volume>:<fpage>52ra73</fpage>. <pub-id pub-id-type="doi">10.1126/scitranslmed.3001059</pub-id><pub-id pub-id-type="pmid">20926834</pub-id></citation></ref>
</ref-list>
</back>
</article>
