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21 citations
Original Research
11 February 2021
13,176 views
45 citations
Review
14 December 2020

Parkinson’s disease (PD) is the second most common neurodegenerative disease, characterized by progressive bradykinesia, rigidity, resting tremor, and gait impairment, as well as a spectrum of non-motor symptoms including autonomic and cognitive dysfunction. The cardinal motor symptoms of PD stem from the loss of substantia nigra (SN) dopaminergic (DAergic) neurons, and it remains unclear why SN DAergic neurons are preferentially lost in PD. However, recent identification of several genetic PD forms suggests that mitochondrial and lysosomal dysfunctions play important roles in the degeneration of midbrain dopamine (DA) neurons. In this review, we discuss the interplay of cell-autonomous mechanisms linked to DAergic neuron vulnerability and alpha-synuclein homeostasis. Emerging studies highlight a deleterious feedback cycle, with oxidative stress, altered DA metabolism, dysfunctional lysosomes, and pathological alpha-synuclein species representing key events in the pathogenesis of PD. We also discuss the interactions of alpha-synuclein with toxic DA metabolites, as well as the biochemical links between intracellular iron, calcium, and alpha-synuclein accumulation. We suggest that targeting multiple pathways, rather than individual processes, will be important for developing disease-modifying therapies. In this context, we focus on current translational efforts specifically targeting lysosomal function, as well as oxidative stress via calcium and iron modulation. These efforts could have therapeutic benefits for the broader population of sporadic PD and related synucleinopathies.

9,674 views
51 citations
7,204 views
22 citations
5,969 views
22 citations
Schematic illustration of the discussed conformational states of α-syn. The unfolded, unbound and monomeric α-syn adopts a partially folded intermediate conformation at its very N-terminus upon membrane binding, leaving the NAC domain exposed for potential primary nucleation. Freely available monomeric α-syn could bind to the hypothesized intermediate conformation, facilitating initial lipid-induced amyloid oligomer and fibril formation. Under physiological conditions, α-syn quickly adopts an extended α-helical or a broken-helix conformation, which can also form physiological multimers that cluster synaptic vesicles. A change in the lipid/α-syn ratio, the lipid composition or the fraction of membrane bound vs. unbound α-syn could shift the balance between physiological and pathological paths.
Mini Review
15 September 2020
The Role of Lipids in the Initiation of α-Synuclein Misfolding
Martin Kiechle
1 more and 
Karin M. Danzer

The aggregation of α-synuclein (α-syn) is inseparably connected to Parkinson’s disease (PD). It is now well-established that certain forms of α-syn aggregates, oligomers and fibrils, can exert neurotoxicity in synucleinopathies. With the exception of rare familial forms, the vast majority of PD cases are idiopathic. Understanding the earliest molecular mechanisms that cause initial α-syn misfolding could help to explain why PD affects only some individuals and others not. Factors that chaperone the transition of α-syn’s physiological to pathological function are of particular interest, since they offer opportunities for intervention. The relationship between α-syn and lipids represents one of those factors. Membrane interaction is crucial for normal cellular function, but lipids also induce the aggregation of α-syn, causing cell toxicity. Also, disease-causing or risk-factor mutations in genes related to lipid metabolism like PLA2G6, SCARB2 or GBA1 highlight the close connection between PD and lipids. Despite the clear link, the ambivalent interaction has not been studied sufficiently so far. In this review, we address how α-syn interacts with lipids and how they can act as key factor for orchestrating toxic conversion of α-syn. Furthermore, we will discuss a scenario in which initial α-syn aggregation is determined by shifts in lipid/α-syn ratio as well as by dyshomeostasis of membrane bound/unbound state of α-syn.

10,822 views
47 citations
Summarizing figure. To analyze PD progression during the disease course, patient samples have to be taken from appropriate sources to allow multiple sampling of the same patient. These include biopsies (e.g., rectal biopsies during colonoscopy for cancer screening), serum, plasma or exosomes from blood samples and CSF from lumbar puncture. Biochemical and structural analysis could then link the different aSyn species to different cell types either via structure determination after (multiple rounds of) amplification by PMCA or through the purification of cell-type specific exosomes. Identification of markers that discriminate patients from each other or patients from control individuals could then be mirrored into clinical practice and be linked to patient outcome. Also, the gut microbiome has been shown to be involved in disease pathology and further studies will have to untangle the relationship between PD, aSyn aggregation and gut dysbiosis.
Review
08 September 2020

Parkinson’s disease (PD) is marked by different kinds of pathological features, one hallmark is the aggregation of α-synuclein (aSyn). The development of aSyn pathology in the substantia nigra is associated to the manifestation of motor deficits at the time of diagnosis. However, most of the patients suffer additionally from non-motor symptoms, which may occur already in the prodromal phase of the disease years before PD is diagnosed. Many of these symptoms manifest in the gastrointestinal system (GIT) and some data suggest a potential link to the occurrence of pathological aSyn forms within the GIT. These clinical and pathological findings lead to the idea of a gut-brain route of aSyn pathology in PD. The identification of pathological aSyn in the intestinal system, e.g., by GIT biopsies, is therefore of highest interest for early diagnosis and early intervention in the phase of formation and propagation of aSyn. However, reliable methods to discriminate between physiological and pathological forms of enteral aSyn on the cellular and biochemical level are still missing. Moreover, a better understanding of the physiological function of aSyn within the GIT as well as its structure and pathological aggregation pathways are crucial to understand its role within the enteric nervous system and its spreading from the gut to the brain. In this review, we summarize clinical manifestations of PD in the GIT, and discuss biochemical findings from enteral biopsies. The relevance of pathological aSyn forms, their connection to the gut-brain axis and new developments to identify pathologic forms of aSyn by structural features are critically reviewed.

12,964 views
62 citations
Structure of α-synuclein. The N-terminal domain of α-synuclein is characterized by the presence of repeated lipid-binding sequences and contains the mutation sites linked with familial PD. The central NAC domain is mainly hydrophobic and favors the aggregation process of the protein. The C-terminal acidic tail carries the majority of α-synuclein phosphorylation sites.
Review
04 September 2020

Parkinson’s disease (PD), multiple system atrophy (MSA) and Dementia with Lewy bodies (DLB) represent pathologically similar, progressive neurodegenerative disorders characterized by the pathological aggregation of the neuronal protein α-synuclein. PD and DLB are characterized by the abnormal accumulation and aggregation of α-synuclein in proteinaceous inclusions within neurons named Lewy bodies (LBs) and Lewy neurites (LNs), whereas in MSA α-synuclein inclusions are mainly detected within oligodendrocytes named glial cytoplasmic inclusions (GCIs). The presence of pathologically aggregated α-synuclein along with components of the protein degradation machinery, such as ubiquitin and p62, in LBs and GCIs is considered to underlie the pathogenic cascade that eventually leads to the severe neurodegeneration and neuroinflammation that characterizes these diseases. Importantly, α-synuclein is proposed to undergo pathogenic misfolding and oligomerization into higher-order structures, revealing self-templating conformations, and to exert the ability of “prion-like” spreading between cells. Therefore, the manner in which the protein is produced, is modified within neural cells and is degraded, represents a major focus of current research efforts in the field. Given that α-synuclein protein load is critical to disease pathogenesis, the identification of means to limit intracellular protein burden and halt α-synuclein propagation represents an obvious therapeutic approach in synucleinopathies. However, up to date the development of effective therapeutic strategies to prevent degeneration in synucleinopathies is limited, due to the lack of knowledge regarding the precise mechanisms underlying the observed pathology. This review critically summarizes the recent developed strategies to counteract α-synuclein toxicity, including those aimed to increase protein degradation, to prevent protein aggregation and cell-to-cell propagation, or to engage antibodies against α-synuclein and discuss open questions and unknowns for future therapeutic approaches.

8,777 views
18 citations
Schematic representation of the link between αSyn and actin. Under physiologic conditions αSyn is mainly concentrated at the pre-synapse and interacts with synaptic vesicles at the several stages of the vesicle cycle. At the pre-synapse αSyn-actin interaction was described as being crucial for the trafficking and transport activity of neurotransmitter transporters (Physiologic, Panel 3; A). Additionally, we suggest that the reported αSyn regulation of actin dynamics might contribute for the proper actin-derived functions at the pre-synapse (Physiologic, Panel 3; B). Under pathologic conditions, overexpression and misfolding of αSyn affects several cellular processes. At the cell membrane, extracellular misfolded αSyn uses a pathway culminating in cofilin-1 activation and actin remodeling to enter the cells (Pathologic, Panels 1–3; C). Intracellularly, synaptic dysfunction might occur due to the αSyn-induced stabilization of the actin cytoskeleton (Pathologic, Panel 3; D), through inactivation of cofilin-1 or αSyn-induced cofilin-actin rod formation (Pathologic, Panel 1; E), that also affects axonal transport. Additionally, αSyn interaction with spectrin (Pathologic, Panel 2; F), disrupts the actin cytoskeleton with consequent mislocalization of Drp1 and mitochondrial impairment.
6,131 views
32 citations
Original Research
29 May 2020
α-Synuclein-112 Impairs Synaptic Vesicle Recycling Consistent With Its Enhanced Membrane Binding Properties
Lindsey G. Soll
4 more and 
Jennifer R. Morgan
α-Syn-112 impairs synaptic vesicle recycling. (A,B) Electron micrographs showing a stimulated (20 Hz, 5 min) control synapse and a synapse treated with recombinant human α-syn-112. While control synapses have a large pool of synaptic vesicles (SVs), moderate plasma membrane (PM) evaginations (red dotted line), and few cisternae (C) or clathrin coated structures (circles), those treated with α-syn-112 are dramatically altered with a notable loss of SVs and buildup of PM. Asterisk marks the post-synaptic dendrite. (C,D) 3D reconstructions reveal that excess α-syn-112 induces a substantial loss of SVs, which was compensated by an extensive build up of PM (green), as well as increased numbers of cisternae (magenta) and clathrin-coated pits (CCPs; yellow) and clathrin-coated vesicles (CCVs; white), indicating impaired vesicle endocytosis. (E–G) Micrographs showing effects of α-syn-112 on clathrin- mediated endocytosis. Control synapses have only few CCPs (red circles), while α-syn-112 treated synapses have many CCPs and CCVs (blue circles). Scale bar in (E) applies to (F,G). (H–M) Morphometric analyses showing differences between control and α-syn-112 treated synapses, which are consistent with defects in synaptic vesicle endocytosis. Increase in stage 3 CCPs and stage 4 CCVs (M) indicates impaired vesicle fission and clathrin uncoating, respectively. Bars indicate mean ± SEM from n = 25 to 26 synapses, 2 axons/animals. Asterisks indicate p < 0.05 by Student’s t-test. (N) Total membrane analysis shows redistribution of synaptic membranes by α-syn-112. n.s. = not significant.

Synucleinopathies are neurological disorders associated with α-synuclein overexpression and aggregation. While it is well-established that overexpression of wild type α-synuclein (α-syn-140) leads to cellular toxicity and neurodegeneration, much less is known about other naturally occurring α-synuclein splice isoforms. In this study we provide the first detailed examination of the synaptic effects caused by one of these splice isoforms, α-synuclein-112 (α-syn-112). α-Syn-112 is produced by an in-frame excision of exon 5, resulting in deletion of amino acids 103–130 in the C-terminal region. α-Syn-112 is upregulated in the substantia nigra, frontal cortex, and cerebellum of parkinsonian brains and higher expression levels are correlated with susceptibility to Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple systems atrophy (MSA). We report here that α-syn-112 binds strongly to anionic phospholipids when presented in highly curved liposomes, similar to α-syn-140. However, α-syn-112 bound significantly stronger to all phospholipids tested, including the phosphoinositides. α-Syn-112 also dimerized and trimerized on isolated synaptic membranes, while α-syn-140 remained largely monomeric. When introduced acutely to lamprey synapses, α-syn-112 robustly inhibited synaptic vesicle recycling. Interestingly, α-syn-112 produced effects on the plasma membrane and clathrin-mediated synaptic vesicle endocytosis that were phenotypically intermediate between those caused by monomeric and dimeric α-syn-140. These findings indicate that α-syn-112 exhibits enhanced phospholipid binding and oligomerization in vitro and consequently interferes with synaptic vesicle recycling in vivo in ways that are consistent with its biochemical properties. This study provides additional evidence suggesting that impaired vesicle endocytosis is a cellular target of excess α-synuclein and advances our understanding of potential mechanisms underlying disease pathogenesis in the synucleinopathies.

4,593 views
25 citations
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