<?xml version="1.0" encoding="utf-8"?>
<!DOCTYPE article PUBLIC "-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" "journalpublishing.dtd">
<article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" article-type="research-article" dtd-version="2.3" xml:lang="EN">
<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Neurol.</journal-id>
<journal-title>Frontiers in Neurology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Neurol.</abbrev-journal-title>
<issn pub-type="epub">1664-2295</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fneur.2024.1404492</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Neurology</subject>
<subj-group>
<subject>Original Research</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Peripheral cutaneous synucleinopathy characteristics in genetic Parkinson&#x2019;s disease</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" equal-contrib="yes">
<name><surname>Yuan</surname> <given-names>Yanpeng</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup></xref>
<xref ref-type="author-notes" rid="fn0003"><sup>&#x2020;</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/1086438/overview"/>
<role content-type="https://credit.niso.org/contributor-roles/supervision/"/>
<role content-type="https://credit.niso.org/contributor-roles/software/"/>
<role content-type="https://credit.niso.org/contributor-roles/methodology/"/>
<role content-type="https://credit.niso.org/contributor-roles/investigation/"/>
<role content-type="https://credit.niso.org/contributor-roles/funding-acquisition/"/>
<role content-type="https://credit.niso.org/contributor-roles/formal-analysis/"/>
<role content-type="https://credit.niso.org/contributor-roles/data-curation/"/>
<role content-type="https://credit.niso.org/contributor-roles/conceptualization/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
</contrib>
<contrib contrib-type="author" equal-contrib="yes">
<name><surname>Wang</surname> <given-names>Yangyang</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup></xref>
<xref ref-type="author-notes" rid="fn0003"><sup>&#x2020;</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/1385757/overview"/>
<role content-type="https://credit.niso.org/contributor-roles/validation/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Liu</surname> <given-names>Minglei</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/methodology/"/>
<role content-type="https://credit.niso.org/contributor-roles/investigation/"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Luo</surname> <given-names>Haiyang</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup></xref>
<xref ref-type="aff" rid="aff4"><sup>4</sup></xref>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/methodology/"/>
<role content-type="https://credit.niso.org/contributor-roles/data-curation/"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Liu</surname> <given-names>Xiaojing</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/993331/overview"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/methodology/"/>
<role content-type="https://credit.niso.org/contributor-roles/investigation/"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Li</surname> <given-names>Lanjun</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/597864/overview"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/formal-analysis/"/>
<role content-type="https://credit.niso.org/contributor-roles/data-curation/"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Mao</surname> <given-names>Chengyuan</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup></xref>
<xref ref-type="aff" rid="aff4"><sup>4</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/757418/overview"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/investigation/"/>
<role content-type="https://credit.niso.org/contributor-roles/data-curation/"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Yang</surname> <given-names>Ting</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup></xref>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/methodology/"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Li</surname> <given-names>Shuo</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup></xref>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/methodology/"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Zhang</surname> <given-names>Xiaoyun</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/2004139/overview"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/funding-acquisition/"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Gao</surname> <given-names>Yuan</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup></xref>
<xref ref-type="aff" rid="aff4"><sup>4</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/1437364/overview"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/supervision/"/>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name><surname>Xu</surname> <given-names>Yuming</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup></xref>
<xref ref-type="aff" rid="aff4"><sup>4</sup></xref>
<xref ref-type="corresp" rid="c001"><sup>&#x002A;</sup></xref>
<xref ref-type="author-notes" rid="fn0001"><sup>&#x2020;</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/400478/overview"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
<role content-type="https://credit.niso.org/contributor-roles/visualization/"/>
<role content-type="https://credit.niso.org/contributor-roles/supervision/"/>
<role content-type="https://credit.niso.org/contributor-roles/software/"/>
<role content-type="https://credit.niso.org/contributor-roles/funding-acquisition/"/>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name><surname>Yang</surname> <given-names>Jing</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup></xref>
<xref ref-type="aff" rid="aff4"><sup>4</sup></xref>
<xref ref-type="corresp" rid="c002"><sup>&#x002A;</sup></xref>
<xref ref-type="author-notes" rid="fn0001"><sup>&#x2020;</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/432480/overview"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
<role content-type="https://credit.niso.org/contributor-roles/supervision/"/>
<role content-type="https://credit.niso.org/contributor-roles/software/"/>
<role content-type="https://credit.niso.org/contributor-roles/methodology/"/>
<role content-type="https://credit.niso.org/contributor-roles/funding-acquisition/"/>
</contrib>
</contrib-group>
<aff id="aff1"><sup>1</sup><institution>Department of Neurology, The First Affiliated Hospital of Zhengzhou University</institution>, <addr-line>Zhengzhou, Henan</addr-line>, <country>China</country></aff>
<aff id="aff2"><sup>2</sup><institution>Henan Key Laboratory of Cerebrovascular Diseases, Zhengzhou University</institution>, <addr-line>Zhengzhou, Henan</addr-line>, <country>China</country></aff>
<aff id="aff3"><sup>3</sup><institution>Institute of Neuroscience, Zhengzhou University</institution>, <addr-line>Zhengzhou, Henan</addr-line>, <country>China</country></aff>
<aff id="aff4"><sup>4</sup><institution>NHC Key Laboratory of Prevention and Treatment of Cerebrovascular Disease</institution>, <addr-line>Zhengzhou, Henan</addr-line>, <country>China</country></aff>
<author-notes>
<fn fn-type="edited-by" id="fn0004"><p>Edited by: Hyunjin Park, Sungkyunkwan University, Republic of Korea</p></fn>
<fn fn-type="edited-by" id="fn0005"><p>Reviewed by: VIncenzo Donadio, IRCCS Institute of Neurological Sciences of Bologna (ISNB), Italy</p><p>Raniki Kumari, Johns Hopkins University, United States</p></fn>
<corresp id="c001">&#x002A;Correspondence: Yuming Xu, <email>xuyuming@zzu.edu.cn</email></corresp>
<corresp id="c002">Jing Yang, <email>yangjing9527@126.com</email></corresp>
<fn fn-type="other" id="fn0001"><p><sup>&#x2020;</sup>ORCID: Yuming Xu, <ext-link ext-link-type="uri" xlink:href="https://orcid.org/0000-0003-2689-9897">https://orcid.org/0000-0003-2689-9897</ext-link></p><p>Jing Yang, <ext-link ext-link-type="uri" xlink:href="https://orcid.org/0000-0002-7356-5083">https://orcid.org/0000-0002-7356-5083</ext-link></p></fn>
<fn fn-type="equal" id="fn0003"><p><sup>&#x2020;</sup>These authors have contributed equally to this work and share first authorship</p></fn>
</author-notes>
<pub-date pub-type="epub">
<day>01</day>
<month>05</month>
<year>2024</year>
</pub-date>
<pub-date pub-type="collection">
<year>2024</year>
</pub-date>
<volume>15</volume>
<elocation-id>1404492</elocation-id>
<history>
<date date-type="received">
<day>21</day>
<month>03</month>
<year>2024</year>
</date>
<date date-type="accepted">
<day>16</day>
<month>04</month>
<year>2024</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#x00A9; 2024 Yuan, Wang, Liu, Luo, Liu, Li, Mao, Yang, Li, Zhang, Gao, Xu and Yang.</copyright-statement>
<copyright-year>2024</copyright-year>
<copyright-holder>Yuan, Wang, Liu, Luo, Liu, Li, Mao, Yang, Li, Zhang, Gao, Xu and Yang</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>
<sec id="sec1">
<title>Background</title>
<p>Cutaneous phosphorylated alpha-synuclein (p-&#x03B1;-syn) deposition is an important biomarker of idiopathic Parkinson&#x2019;s disease (iPD). Recent studies have reported synucleinopathies in patients with common genetic forms of PD.</p>
</sec>
<sec id="sec2">
<title>Objective</title>
<p>This study aimed to detect p-&#x03B1;-syn deposition characteristic in rare genetic PD patients with <italic>CHCHD2</italic> or <italic>RAB39B</italic> mutations. Moreover, this study also aimed to describe peripheral alpha-synuclein prion-like activity in genetic PD patients, and acquire whether the cutaneous synucleinopathy characteristics of genetic PD are consistent with central neuropathologies.</p>
</sec>
<sec id="sec3">
<title>Methods</title>
<p>We performed four skin biopsy samples from the distal leg (DL) and proximal neck (C7) of 161 participants, including four patients with <italic>CHCHD2</italic> mutations, two patients with <italic>RAB39B</italic> mutations, 16 patients with <italic>PRKN</italic> mutations, 14 patients with <italic>LRRK2</italic> mutations, five patients with <italic>GBA</italic> mutations, 100 iPD patients, and 20 healthy controls. We detected cutaneous synucleinopathies using immunofluorescence staining and a seeding amplification assay (SAA). A systematic literature review was also conducted, involving 64 skin biopsies and 205 autopsies of genetic PD patients with synucleinopathy.</p>
</sec>
<sec id="sec4">
<title>Results</title>
<p>P-&#x03B1;-syn was deposited in the peripheral cutaneous nerves of PD patients with <italic>CHCHD2</italic>, <italic>LRRK2</italic>, or <italic>GBA</italic> mutations but not in those with <italic>RAB39B</italic> or <italic>PRKN</italic> mutations. There were no significant differences in the location or rate of &#x03B1;-syn-positive deposits between genetic PD and iPD patients. Peripheral cutaneous synucleinopathy appears to well represent brain synucleinopathy of genetic PD, especially autosomal dominant PD (AD-PD). Cutaneous &#x03B1;-synuclein SAA analysis of iPD and <italic>LRRK2</italic> and <italic>GBA</italic> mutation patients revealed prion-like activity.</p>
</sec>
<sec id="sec5">
<title>Conclusion</title>
<p>P-&#x03B1;-syn deposition in peripheral cutaneous nerves, detected using SAA and immunofluorescence staining, may serve as an accurate biomarker for genetic PD and iPD in the future.</p>
</sec>
</abstract>
<kwd-group>
<kwd>skin biopsy</kwd>
<kwd>genetic Parkinson&#x2019;s disease</kwd>
<kwd>SAA</kwd>
<kwd>&#x03B1;-synuclein</kwd>
<kwd>
<italic>CHCHD2</italic>
</kwd>
<kwd>
<italic>RAB39B</italic>
</kwd>
</kwd-group>
<counts>
<fig-count count="5"/>
<table-count count="6"/>
<equation-count count="0"/>
<ref-count count="90"/>
<page-count count="16"/>
<word-count count="10307"/>
</counts>
<custom-meta-wrap>
<custom-meta>
<meta-name>section-at-acceptance</meta-name>
<meta-value>Movement Disorders</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec sec-type="intro" id="sec6">
<title>Introduction</title>
<p>Parkinson&#x2019;s disease (PD) is a common neurodegenerative disorder caused by interactions among genetic and environmental risk factors (<xref ref-type="bibr" rid="ref1">1</xref>). Approximately 15% of PD patients have a family history of the disease, with 5&#x2013;10% presenting with a pattern of monogenic inheritance (<xref ref-type="bibr" rid="ref2">2</xref>). The most common genetic risk factors for PD include <italic>SNCA</italic>, <italic>LRRK2</italic>, <italic>PRKN</italic>, <italic>GBA</italic>, and <italic>DJ-1</italic>, which are also associated with heterogeneous neuropathology and possibly with alpha-synuclein (&#x03B1;-syn)-positive Lewy body pathology (<xref ref-type="bibr" rid="ref3 ref4 ref5 ref6 ref7 ref8">3&#x2013;8</xref>). Cutaneous phosphorylated &#x03B1;-syn (p-&#x03B1;-syn) deposits have been detected in PD patients in recent years, highlighting their potential as biomarkers for premortem diagnosis (<xref ref-type="bibr" rid="ref9">9</xref>). Cutaneous synucleinopathy has also been observed in PD patients with common genetic risk factors, including <italic>SNCA</italic>, <italic>LRRK2</italic>, <italic>GBA</italic>, and <italic>DJ-1</italic> (<xref ref-type="bibr" rid="ref8">8</xref>, <xref ref-type="bibr" rid="ref10 ref11 ref12 ref13">10&#x2013;13</xref>). Our research group previously identified two rare genes, <italic>CHCHD2</italic> T61I and <italic>RAB39B</italic> E179fsX48, in two Chinese families (<xref ref-type="bibr" rid="ref14">14</xref>, <xref ref-type="bibr" rid="ref15">15</xref>). Features of synucleinopathy at autopsy have also been reported in patients harboring mutations at analogous sites (<xref ref-type="bibr" rid="ref16 ref17 ref18">16&#x2013;18</xref>). However, the presence of cutaneous synucleinopathy in PD patients with <italic>CHCHD2</italic> and <italic>RAB39B</italic> mutations has not yet to be determined.</p>
<p>Seeding amplification assay (SAA) were initially developed as specific and quantitative diagnostic tests for prion diseases (<xref ref-type="bibr" rid="ref19">19</xref>). Recent applications have demonstrated the ability of SAA to detect the seeding activity of misfolded &#x03B1;-syn in the brain, cerebrospinal fluid (CSF), and skin samples from individuals with PD and Lewy body disease (LBD), achieving sensitivity rates of 92 to 95% and specificity rates of 98% to 100% (<xref ref-type="bibr" rid="ref20 ref21 ref22 ref23">20&#x2013;23</xref>). However, the efficacy of SAA in sensitively detecting &#x03B1;-syn prion-like activity in the skin of patients with genetic PD has not yet been established.</p>
<p>At present, substantia nigra pars compacta (SNpc) neuronal degeneration and Lewy body pathology within the brainstem remain critical hallmarks for the diagnosis of PD (<xref ref-type="bibr" rid="ref1">1</xref>). Consequently, the identification of peripheral biomarkers of PD has emerged as a significant area of research interest. Several studies have shown that skin synucleinopathies in PD patients closely mirror intracranial pathologies, both in terms of morphology and main synuclein components (<xref ref-type="bibr" rid="ref9">9</xref>, <xref ref-type="bibr" rid="ref24">24</xref>, <xref ref-type="bibr" rid="ref25">25</xref>), highlighting their considerable potential in peripheral biomarker research. To date, however, few studies have explored the characteristics of peripheral skin synucleinopathy in genetic PD, with no definitive evidence confirming the consistency between cutaneous and intracranial synucleinopathy alterations.</p>
<p>Hence, in the current study, we aimed to investigate cutaneous synucleinopathy in PD patients with <italic>CHCHD2</italic> and <italic>RAB39B</italic> mutations, explore &#x03B1;-syn prion-like activity in the skin of patients with genetic PD, and assess whether the peripheral cutaneous synucleinopathy observed in genetic PD is consistent with central neuropathology.</p>
</sec>
<sec sec-type="materials|methods" id="sec7">
<title>Materials and methods</title>
<sec id="sec8">
<title>Subjects and clinical assessment</title>
<p>A total of 161 participants were enrolled in this study. The cohort included four patients from one family with the <italic>CHCHD2</italic> T61I mutation; two patients from one family with the <italic>RAB39B</italic> E179fsX48 mutation; 16 patients with <italic>PRKN</italic> mutations; 14 patients with <italic>LRRK2</italic> mutations; five patients with <italic>GBA</italic> mutations; 100 idiopathic PD (iPD) patients with no known PD-associated mutations; and 20 healthy controls (<xref ref-type="table" rid="tab1">Table 1</xref>). The two families with the <italic>CHCHD2</italic> T61I and <italic>RAB39B</italic> E179fsX48 mutations have been described in our previous studies (<xref ref-type="bibr" rid="ref14">14</xref>, <xref ref-type="bibr" rid="ref15">15</xref>). All patients were recruited from the First Affiliated Hospital of Zhengzhou University (China) and fulfilled the Movement Disorder Society Clinical Diagnostic Criteria for PD (<xref ref-type="bibr" rid="ref26">26</xref>). All participants underwent detailed neurological examination. Motor impairment was evaluated using the Movement Disorder Society Unified PD Rating Scale, part III (MDS-UPDRS-III) (<xref ref-type="bibr" rid="ref27">27</xref>). Disease stage was assessed using the Hoehn &#x0026; Yahr scale (<xref ref-type="bibr" rid="ref28">28</xref>). Autonomic dysfunction and other nonmotor symptoms were evaluated using the nonmotor symptoms scale (NMSS) (<xref ref-type="bibr" rid="ref29">29</xref>).</p>
<table-wrap position="float" id="tab1">
<label>Table 1</label>
<caption>
<p>Demographics and clinical characteristics of patients and healthy controls.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th/>
<th align="center" valign="top"><italic>CHCHD2</italic></th>
<th align="center" valign="top"><italic>RAB39B</italic></th>
<th align="center" valign="top"><italic>PRKN</italic></th>
<th align="center" valign="top"><italic>LRRK2</italic></th>
<th align="center" valign="top"><italic>GBA</italic></th>
<th align="center" valign="top">iPD</th>
<th align="center" valign="top">HC</th>
</tr>
<tr>
<th/>
<th align="center" valign="bottom">(<italic>n</italic> =&#x2009;4)</th>
<th align="center" valign="bottom">(<italic>n</italic> =&#x2009;2)</th>
<th align="center" valign="bottom">(<italic>n</italic> =&#x2009;16)</th>
<th align="center" valign="top">(<italic>n</italic> =&#x2009;14)</th>
<th align="center" valign="top">(<italic>n</italic> =&#x2009;5)</th>
<th align="center" valign="bottom">(<italic>n</italic> =&#x2009;100)</th>
<th align="center" valign="bottom">(<italic>n</italic> =&#x2009;20)</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="bottom">Age (y)</td>
<td align="center" valign="bottom">48.50&#x2009;&#x00B1;&#x2009;12.79</td>
<td align="center" valign="top">43.50&#x2009;&#x00B1;&#x2009;26.16</td>
<td align="center" valign="bottom">37.94&#x2009;&#x00B1;&#x2009;8.59</td>
<td align="center" valign="top">61.79&#x2009;&#x00B1;&#x2009;8.20</td>
<td align="center" valign="top">44.60&#x2009;&#x00B1;&#x2009;10.58</td>
<td align="center" valign="bottom">64.07&#x2009;&#x00B1;&#x2009;9.16</td>
<td align="center" valign="bottom">55.35&#x2009;&#x00B1;&#x2009;9.03</td>
</tr>
<tr>
<td align="left" valign="bottom">Sex, male, <italic>n</italic> (%)</td>
<td align="center" valign="bottom">3 (75%)</td>
<td align="center" valign="top">2 (100%)</td>
<td align="center" valign="bottom">10 (62.50%)</td>
<td align="center" valign="top">4 (28.57%)</td>
<td align="center" valign="top">2(40%)</td>
<td align="center" valign="bottom">59 (59%)</td>
<td align="center" valign="bottom">10 (50%)</td>
</tr>
<tr>
<td align="left" valign="bottom">AAO (y)</td>
<td align="center" valign="bottom">41.75&#x2009;&#x00B1;&#x2009;9.18</td>
<td align="center" valign="top">11.00&#x2009;&#x00B1;&#x2009;1.41</td>
<td align="center" valign="bottom">28.06&#x2009;&#x00B1;&#x2009;8.42</td>
<td align="center" valign="top">49.61&#x2009;&#x00B1;&#x2009;7.14</td>
<td align="center" valign="top">41.20&#x2009;&#x00B1;&#x2009;10.21</td>
<td align="center" valign="bottom">58.72&#x2009;&#x00B1;&#x2009;10.07</td>
<td align="center" valign="bottom">/</td>
</tr>
<tr>
<td align="left" valign="bottom">Disease duration (y)</td>
<td align="center" valign="bottom">6.75&#x2009;&#x00B1;&#x2009;4.11</td>
<td align="center" valign="top">32.00&#x2009;&#x00B1;&#x2009;28.28</td>
<td align="center" valign="bottom">9.88&#x2009;&#x00B1;&#x2009;6.53</td>
<td align="center" valign="top">7.72&#x2009;&#x00B1;&#x2009;6.39</td>
<td align="center" valign="top">3.40&#x2009;&#x00B1;&#x2009;2.30</td>
<td align="center" valign="bottom">5.35&#x2009;&#x00B1;&#x2009;4.46</td>
<td align="center" valign="bottom">/</td>
</tr>
<tr>
<td align="left" valign="bottom">Hoehn and Yahr stage</td>
<td align="center" valign="bottom">1.63&#x2009;&#x00B1;&#x2009;0.75</td>
<td align="center" valign="top">2.75&#x2009;&#x00B1;&#x2009;0.35</td>
<td align="center" valign="bottom">2.41&#x2009;&#x00B1;&#x2009;0.86</td>
<td align="center" valign="top">2.53&#x2009;&#x00B1;&#x2009;0.50</td>
<td align="center" valign="top">2.00&#x2009;&#x00B1;&#x2009;0.00</td>
<td align="center" valign="bottom">2.55&#x2009;&#x00B1;&#x2009;0.97</td>
<td align="center" valign="bottom">/</td>
</tr>
<tr>
<td align="left" valign="bottom">MDS-UPDRS-III</td>
<td align="center" valign="bottom">21.25&#x2009;&#x00B1;&#x2009;17.11</td>
<td align="center" valign="top">41.50&#x2009;&#x00B1;&#x2009;23.33</td>
<td align="center" valign="bottom">32.88&#x2009;&#x00B1;&#x2009;14.48</td>
<td align="center" valign="top">48.72&#x2009;&#x00B1;&#x2009;28.16</td>
<td align="center" valign="top">23&#x2009;&#x00B1;&#x2009;13.06</td>
<td align="center" valign="bottom">43.51&#x2009;&#x00B1;&#x2009;19.18</td>
<td align="center" valign="bottom">/</td>
</tr>
<tr>
<td align="left" valign="bottom">NMSS score</td>
<td align="center" valign="bottom">71.25&#x2009;&#x00B1;&#x2009;57.28</td>
<td align="center" valign="top">8.00&#x2009;&#x00B1;&#x2009;0.00</td>
<td align="center" valign="bottom">13.69&#x2009;&#x00B1;&#x2009;14.27</td>
<td align="center" valign="top">53.64&#x2009;&#x00B1;&#x2009;22.74</td>
<td align="center" valign="top">16.00&#x2009;&#x00B1;&#x2009;14.98</td>
<td align="center" valign="bottom">54.87&#x2009;&#x00B1;&#x2009;46.51</td>
<td align="center" valign="bottom">/</td>
</tr>
<tr>
<td align="left" valign="bottom">RBD, <italic>n</italic> (%)</td>
<td align="center" valign="bottom">0 (0%)</td>
<td align="center" valign="top">1 (50%)</td>
<td align="center" valign="bottom">1 (6.67%)</td>
<td align="center" valign="top">8 (57.14%)</td>
<td align="center" valign="top">0(0%)</td>
<td align="center" valign="bottom">25 (25%)</td>
<td align="center" valign="bottom">0 (0%)</td>
</tr>
<tr>
<td align="left" valign="bottom">MMSE score</td>
<td align="center" valign="bottom">27.50&#x2009;&#x00B1;&#x2009;3.00</td>
<td align="center" valign="top">19.00&#x2009;&#x00B1;&#x2009;8.49</td>
<td align="center" valign="bottom">27.88&#x2009;&#x00B1;&#x2009;1.59</td>
<td align="center" valign="top">26.47&#x2009;&#x00B1;&#x2009;1.29</td>
<td align="center" valign="top">27.40&#x2009;&#x00B1;&#x2009;0.89</td>
<td align="center" valign="bottom">26.70&#x2009;&#x00B1;&#x2009;3.25</td>
<td align="center" valign="bottom">27.35&#x2009;&#x00B1;&#x2009;2.08</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p><italic>CHCHD2</italic>, coiled-coil-helix-coil-helix domain containing 2; <italic>RAB39B</italic>, Ras analog in brain 39b; <italic>GBA</italic>, glucocerebrosidase; <italic>PRKN</italic>, Parkin RBR E3 ubiquitin protein ligase; <italic>LRRK2</italic>, leucine-rich repeat kinase 2; iPD, idiopathic Parkinson&#x2019;s disease; HC, healthy control; AAO, age at onset; MDS-UPDRS III, Movement Disorder Society Unified Parkinson&#x2019;s Disease Ranking Scale part III; NMSS, nonmotor symptoms scale; RBD, rapid eye movement sleep behavior disorder; MMSE, Mini-Mental State Examination Scale.</p>
</table-wrap-foot>
</table-wrap>
<p>This study was approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (2019-KY-294). All work was carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. All participants provided written informed consent to participate.</p>
</sec>
<sec id="sec9">
<title>Skin biopsy</title>
<p>Skin punch biopsies (3&#x2009;mm in diameter, four samples) were taken from the distal leg (DL) (two samples) and proximal neck region (C7) (two samples) of the 161 participants under 20&#x2009;mg/mL lidocaine local anesthesia using a sterile technique according to current guidelines (<xref ref-type="bibr" rid="ref9">9</xref>). The two samples were parallel. There were 5&#x2009;mm distance between two samples. The four obtained biopsies included the epidermis and subpapillary dermis. Biopsy specimens were immediately immersion-fixed with Zamboni solution (G2190; Solarbio, China) for 12&#x2013;24&#x2009;h. The fixation buffer was changed to tissue cryoprotectant solution until use. The biopsy tissues were sliced into 50-&#x03BC;m sections using a frozen slicer (Leica CM1950, Mannheim, Germany).</p>
</sec>
<sec id="sec10">
<title>Brain autopsy cases</title>
<p>A systematic literature review of brain autopsy cases was conducted using the terms &#x201C;autopsy,&#x201D; &#x201C;genetic Parkinson&#x2019;s disease,&#x201D; &#x201C;&#x03B1;-synuclein,&#x201D; &#x201C;Lewy body pathology,&#x201D; &#x201C;brain pathology,&#x201D; and &#x201C;synucleinopathy,&#x201D; as well as specific gene nomenclature (<italic>CHCHD2</italic>, <italic>RAB39B</italic>, <italic>PRKN/PARK2/Parkin</italic>, <italic>LRRK2</italic>, <italic>GBA</italic>, <italic>SNCA</italic>, and <italic>DJ-1</italic>), and any combination of the above.</p>
</sec>
<sec id="sec11">
<title>Immunofluorescence staining</title>
<p>Free-floating immunofluorescence was performed on one of every five 50-&#x03BC;m thick serial sections of skin biopsies, as described previously (<xref ref-type="bibr" rid="ref13">13</xref>). To evaluate the intra-axonal localization of p-&#x03B1;-syn deposits, four additional 50&#x2009;&#x03BC;m thickness sections at 200&#x2009;&#x03BC;m interval from each skin samples, double-labeling immunofluorescence analysis of all patients and controls was conducted using the anti-protein-encoding gene product 9.5 (PGP9.5), anti-p-&#x03B1;-syn (p-syn), anti-calcitonin gene-related peptide (CGRP), anti-tyrosine hydroxylase (TH), anti-vasoactive intestinal peptide (VIP), anti-&#x03B1;-syn, anti-5G4, anti-ASyO5, anti-AT8, anti-HT7, anti-TDP-43, anti-ubiquitin, anti-A&#x03B2;40, and anti-A&#x03B2;42 (see <xref ref-type="supplementary-material" rid="SM1">1Supplementary Table S1</xref> for detailed antibody information). The secondary antibodies used included Alexa Fluor 594-conjugated goat anti-mouse/rabbit immunoglobulin G (IgG) (Origene, China, 1:400) and Alexa Fluor 488-conjugated goat anti-rabbit/mouse IgG (Origene, China, 1:800). Photomicrographs were taken using a confocal laser scanning microscope (Nikon, A1 HD25, Japan) and fluorescence microscope (Nikon, Eclipse Ni, Japan).</p>
<p>The immunostaining should be repeated when negative signal was found for the first time. The immunostaining results were considered &#x201C;positive&#x201D; when PGP9.5 was colocalized with anti-p-&#x03B1;-syn, anti-ASyO5, anti-5G4, anti-&#x03B1;-synuclein, anti-AT8, anti-HT7, anti-TDP-43, anti-ubiquitin, anti-A&#x03B2;40, or anti-A&#x03B2;42 in skin biopsy nerve fibers. The immunostaining results were also considered &#x201C;positive&#x201D; when p-syn was colocalized with anti-CGRP, anti-TH and anti-VIP in skin biopsy nerve fibers.</p>
</sec>
<sec id="sec12">
<title>Preparation of skin tissues for SAA</title>
<p>Skin tissue preparation was conducted as described previously (<xref ref-type="bibr" rid="ref22">22</xref>). Briefly, skin tissues were washed three times in 1&#x00D7; Tris (hydroxymethyl) aminomethane-buffered saline and chopped into small pieces. Skin homogenates (10%, weight/volume) were prepared in skin lysis buffer containing 2&#x2009;mmol of calcium chloride and 0.25% (weight/volume) collagenase A (Roche, 10,103,586,001, Germany) in Tris-buffered saline and incubated in a shaker at 37&#x00B0;C for 4&#x2009;h, followed by homogenization in a Mini-Beadbeater (BioSpec; Laboratory Supply Network) for 1&#x2009;min. After sonication to disrupt the remaining tissue structures, the samples were centrifuged for 5&#x2009;min at 500&#x2009;&#x00D7;&#x2009;<italic>g</italic> for collection of the supernatant fraction.</p>
</sec>
<sec id="sec13">
<title>Seeding amplification assay</title>
<p>The SAA was conducted as described previously (<xref ref-type="bibr" rid="ref22">22</xref>), with some modifications. Briefly, the SAA reaction mixture was composed of 40&#x2009;mM phosphate buffer (pH 8.0), 170&#x2009;mM NaCl, 0.1&#x2009;mg/mL recombinant human wild-type &#x03B1;-syn, 10&#x2009;&#x03BC;M thioflavinT (ThT) (Sigma, T3516-5G, Germany), and 0.00125% sodium dodecyl sulfate. Reaction mixture aliquots (98&#x2009;&#x03BC;L) were loaded into each well of a black 96-well plate with a clear bottom (Nunc) preloaded with 800&#x2009;&#x03BC;m Silica beads (OPS Diagnostics, 800-200-01, United States), with the cells then seeded with 2&#x2009;&#x03BC;L of skin homogenate.</p>
</sec>
<sec id="sec14">
<title>Statistical analysis</title>
<p>All data are expressed as means &#x00B1; standard deviation (SD) or percentages. All statistical analyses were carried out using GraphPad Prism 6 (GraphPad Software, La Jolla California, United States). Independent sample <italic>t</italic>-test or Mann&#x2013;Whitney U test was used to analyze continuous variables and chi-square test was used to analyze categorical variables. Differences were considered statistically significant at <italic>p</italic>&#x2009;&#x003C;&#x2009;0.05.</p>
</sec>
</sec>
<sec sec-type="results" id="sec15">
<title>Results</title>
<sec id="sec16">
<title>Genetic and clinical features of genetic PD patients</title>
<p>The <italic>CHCHD2</italic> T61I mutation was identified in a family with autosomal dominant PD. Individuals with this mutation exhibited typical parkinsonism, although one patient only exhibited simple tremor. The mean age at onset (AAO) was 39.33&#x2009;&#x00B1;&#x2009;8.50&#x2009;years, and the mean disease duration was 4.67&#x2009;&#x00B1;&#x2009;3.21&#x2009;years (<xref ref-type="table" rid="tab1">Tables 1</xref>, <xref ref-type="table" rid="tab2">2</xref>). Patients exhibited mild motor symptoms but severe nonmotor symptoms, including orthostatic hypotension, constipation, depression, smell impairment, and sexual dysfunction. A positive response to levodopa treatment was observed in all four patients.</p>
<table-wrap position="float" id="tab2">
<label>Table 2</label>
<caption>
<p>Genetic and clinical features of patients with genetic PD.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left" valign="top">Gene</th>
<th align="left" valign="top">Mutation sites</th>
<th align="center" valign="top">Sex</th>
<th align="center" valign="top">Age (y)</th>
<th align="center" valign="top">AAO (y)</th>
<th align="left" valign="top">Initial symptoms</th>
<th align="center" valign="top">Disease duration (y)</th>
<th align="center" valign="top">H&#x0026;Y stage</th>
<th align="center" valign="top">MDS-UPDRS III score</th>
<th align="center" valign="top">NMSS score</th>
<th align="center" valign="top">RBD</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="bottom"><italic>CHCHD2</italic></td>
<td align="left" valign="bottom">p. T61I</td>
<td align="center" valign="bottom">M</td>
<td align="center" valign="bottom">54</td>
<td align="center" valign="bottom">48</td>
<td align="left" valign="bottom">Resting tremor</td>
<td align="center" valign="bottom">6</td>
<td align="center" valign="bottom">2</td>
<td align="center" valign="bottom">28</td>
<td align="center" valign="bottom">135</td>
<td align="center" valign="bottom">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>CHCHD2</italic></td>
<td align="left" valign="bottom">p. T61I</td>
<td align="center" valign="bottom">M</td>
<td align="center" valign="bottom">46</td>
<td align="center" valign="bottom">39</td>
<td align="left" valign="bottom">Essential tremor</td>
<td align="center" valign="bottom">7</td>
<td align="center" valign="bottom">1</td>
<td align="center" valign="bottom">4</td>
<td align="center" valign="bottom">28</td>
<td align="center" valign="bottom">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>CHCHD2</italic></td>
<td align="left" valign="bottom">p. T61I</td>
<td align="center" valign="bottom">M</td>
<td align="center" valign="bottom">32</td>
<td align="center" valign="bottom">30</td>
<td align="left" valign="bottom">Resting tremor</td>
<td align="center" valign="bottom">2</td>
<td align="center" valign="bottom">1</td>
<td align="center" valign="bottom">5</td>
<td align="center" valign="bottom">30</td>
<td align="center" valign="bottom">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>CHCHD2</italic></td>
<td align="left" valign="bottom">p. T61I</td>
<td align="center" valign="bottom">F</td>
<td align="center" valign="bottom">62</td>
<td align="center" valign="bottom">50</td>
<td align="left" valign="bottom">Resting tremor</td>
<td align="center" valign="bottom">12</td>
<td align="center" valign="bottom">2.5</td>
<td align="center" valign="bottom">42</td>
<td align="center" valign="bottom">104</td>
<td align="center" valign="bottom">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>RAB39B</italic></td>
<td align="left" valign="bottom">p. E179fsX48</td>
<td align="center" valign="bottom">M</td>
<td align="center" valign="bottom">24</td>
<td align="center" valign="bottom">12</td>
<td align="left" valign="bottom">Resting tremor</td>
<td align="center" valign="bottom">12</td>
<td align="center" valign="bottom">2.5</td>
<td align="center" valign="bottom">25</td>
<td align="center" valign="bottom">8</td>
<td align="center" valign="bottom">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>RAB39B</italic></td>
<td align="left" valign="bottom">p. E179fsX48</td>
<td align="center" valign="bottom">M</td>
<td align="center" valign="bottom">62</td>
<td align="center" valign="bottom">10</td>
<td align="left" valign="bottom">Resting tremor</td>
<td align="center" valign="bottom">52</td>
<td align="center" valign="bottom">3</td>
<td align="center" valign="bottom">58</td>
<td align="center" valign="bottom">8</td>
<td align="center" valign="bottom">+</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>PRKN</italic></td>
<td align="left" valign="bottom">E3-4 del; p. G284R</td>
<td align="center" valign="bottom">F</td>
<td align="center" valign="bottom">31</td>
<td align="center" valign="bottom">21</td>
<td align="left" valign="bottom">Bradykinesia-rigidity</td>
<td align="center" valign="bottom">10</td>
<td align="center" valign="bottom">3</td>
<td align="center" valign="bottom">47</td>
<td align="center" valign="bottom">59</td>
<td align="center" valign="bottom">+</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>PRKN</italic></td>
<td align="left" valign="middle">E4 del; p. G284R</td>
<td align="center" valign="bottom">M</td>
<td align="center" valign="bottom">40</td>
<td align="center" valign="bottom">27</td>
<td align="left" valign="bottom">Bradykinesia-rigidity</td>
<td align="center" valign="bottom">13</td>
<td align="center" valign="bottom">2</td>
<td align="center" valign="bottom">18</td>
<td align="center" valign="bottom">8</td>
<td align="center" valign="bottom">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>PRKN</italic></td>
<td align="left" valign="bottom">E6-7 del; p.E309&#x002A;</td>
<td align="center" valign="bottom">M</td>
<td align="center" valign="bottom">26</td>
<td align="center" valign="bottom">11</td>
<td align="left" valign="bottom">Bradykinesia-rigidity</td>
<td align="center" valign="bottom">15</td>
<td align="center" valign="bottom">2</td>
<td align="center" valign="bottom">39</td>
<td align="center" valign="bottom">3</td>
<td align="center" valign="bottom">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>PRKN</italic></td>
<td align="left" valign="bottom">E2-3 del; c.2T&#x003E;C</td>
<td align="center" valign="bottom">F</td>
<td align="center" valign="bottom">42</td>
<td align="center" valign="bottom">36</td>
<td align="left" valign="bottom">Resting tremor</td>
<td align="center" valign="bottom">6</td>
<td align="center" valign="bottom">3</td>
<td align="center" valign="bottom">36</td>
<td align="center" valign="bottom">36</td>
<td align="center" valign="bottom">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>PRKN</italic></td>
<td align="left" valign="bottom">E3 del; E6 del</td>
<td align="center" valign="bottom">F</td>
<td align="center" valign="bottom">41</td>
<td align="center" valign="bottom">36</td>
<td align="left" valign="bottom">Bradykinesia-rigidity</td>
<td align="center" valign="bottom">5</td>
<td align="center" valign="bottom">2</td>
<td align="center" valign="bottom">14</td>
<td align="center" valign="bottom">7</td>
<td align="center" valign="bottom">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>PRKN</italic></td>
<td align="left" valign="bottom">E3 del; E7 del</td>
<td align="center" valign="bottom">M</td>
<td align="center" valign="bottom">47</td>
<td align="center" valign="bottom">37</td>
<td align="left" valign="bottom">Bradykinesia</td>
<td align="center" valign="bottom">10</td>
<td align="center" valign="bottom">3</td>
<td align="center" valign="bottom">65</td>
<td align="center" valign="bottom">17</td>
<td align="center" valign="bottom">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>PRKN</italic></td>
<td align="left" valign="bottom">E3 del; E5 del</td>
<td align="center" valign="bottom">M</td>
<td align="center" valign="bottom">29</td>
<td align="center" valign="bottom">25</td>
<td align="left" valign="bottom">Resting tremor</td>
<td align="center" valign="bottom">4</td>
<td align="center" valign="bottom">2.5</td>
<td align="center" valign="bottom">41</td>
<td align="center" valign="bottom">8</td>
<td align="center" valign="bottom">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>PRKN</italic></td>
<td align="left" valign="bottom">E3 del; c.1310delC</td>
<td align="center" valign="bottom">F</td>
<td align="center" valign="bottom">29</td>
<td align="center" valign="bottom">26</td>
<td align="left" valign="bottom">Rigidity</td>
<td align="center" valign="bottom">3</td>
<td align="center" valign="bottom">3</td>
<td align="center" valign="bottom">26</td>
<td align="center" valign="bottom">10</td>
<td align="center" valign="bottom">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>PRKN</italic></td>
<td align="left" valign="bottom">E2-4 dup</td>
<td align="center" valign="bottom">F</td>
<td align="center" valign="bottom">36</td>
<td align="center" valign="bottom">20</td>
<td align="left" valign="bottom">Bradykinesia-rigidity</td>
<td align="center" valign="bottom">16</td>
<td align="center" valign="bottom">2</td>
<td align="center" valign="bottom">38</td>
<td align="center" valign="bottom">21</td>
<td align="center" valign="bottom">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>PRKN</italic></td>
<td align="left" valign="bottom">p.S223&#x002A;; E2 del</td>
<td align="center" valign="bottom">M</td>
<td align="center" valign="bottom">28</td>
<td align="center" valign="bottom">20</td>
<td align="left" valign="bottom">Resting tremor-Rigidity</td>
<td align="center" valign="bottom">8</td>
<td align="center" valign="bottom">2</td>
<td align="center" valign="bottom">26</td>
<td align="center" valign="bottom">6</td>
<td align="center" valign="bottom">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>PRKN</italic></td>
<td align="left" valign="bottom">c. 933&#x2009;+&#x2009;5G&#x203A;T Homo</td>
<td align="center" valign="bottom">F</td>
<td align="center" valign="bottom">57</td>
<td align="center" valign="bottom">31</td>
<td align="left" valign="bottom">Bradykinesia</td>
<td align="center" valign="bottom">26</td>
<td align="center" valign="bottom">3</td>
<td align="center" valign="bottom">37</td>
<td align="center" valign="bottom">18</td>
<td align="center" valign="bottom">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>PRKN</italic></td>
<td align="left" valign="bottom">E3 del; E4 del</td>
<td align="center" valign="bottom">M</td>
<td align="center" valign="bottom">44</td>
<td align="center" valign="bottom">36</td>
<td align="left" valign="bottom">Resting tremor</td>
<td align="center" valign="bottom">8</td>
<td align="center" valign="bottom">2</td>
<td align="center" valign="bottom">15</td>
<td align="center" valign="bottom">2</td>
<td align="center" valign="bottom">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>PRKN</italic></td>
<td align="left" valign="bottom">p.S286 Profs&#x002A;12; E3 duplication</td>
<td align="center" valign="bottom">M</td>
<td align="center" valign="bottom">48</td>
<td align="center" valign="bottom">33</td>
<td align="left" valign="bottom">Resting tremor</td>
<td align="center" valign="bottom">15</td>
<td align="center" valign="bottom">2.5</td>
<td align="center" valign="bottom">54</td>
<td align="center" valign="bottom">0</td>
<td align="center" valign="bottom">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>PRKN</italic></td>
<td align="left" valign="bottom">splice-3, E3-4 del</td>
<td align="center" valign="bottom">M</td>
<td align="center" valign="bottom">32</td>
<td align="center" valign="bottom">31</td>
<td align="left" valign="bottom">Bradykinesia</td>
<td align="center" valign="bottom">1</td>
<td align="center" valign="bottom">2</td>
<td align="center" valign="bottom">15</td>
<td align="center" valign="bottom">6</td>
<td align="center" valign="bottom">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>PRKN</italic></td>
<td align="left" valign="bottom">E3-4 del, E7 del</td>
<td align="center" valign="bottom">M</td>
<td align="center" valign="bottom">33</td>
<td align="center" valign="bottom">17</td>
<td align="left" valign="bottom">Bradykinesia</td>
<td align="center" valign="bottom">16</td>
<td align="center" valign="bottom">2</td>
<td align="center" valign="bottom">22</td>
<td align="center" valign="bottom">29</td>
<td align="center" valign="bottom">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>PRKN</italic></td>
<td align="left" valign="bottom">E5-6 dup, c.2T&#x003E;C</td>
<td align="center" valign="bottom">M</td>
<td align="center" valign="bottom">44</td>
<td align="center" valign="bottom">41</td>
<td align="left" valign="bottom">Bradykinesia</td>
<td align="center" valign="bottom">3</td>
<td align="center" valign="bottom">2</td>
<td align="center" valign="bottom">35</td>
<td align="center" valign="bottom">8</td>
<td align="center" valign="bottom">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>GBA</italic></td>
<td align="left" valign="bottom">p.L483P</td>
<td align="center" valign="bottom">F</td>
<td align="center" valign="top">32</td>
<td align="center" valign="top">25</td>
<td align="left" valign="top">Resting tremor</td>
<td align="center" valign="top">7</td>
<td align="center" valign="top">2</td>
<td align="center" valign="top">34</td>
<td align="center" valign="top">1</td>
<td align="center" valign="top">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="top"><italic>GBA</italic></td>
<td align="left" valign="top">p.A502C</td>
<td align="center" valign="top">M</td>
<td align="center" valign="top">42</td>
<td align="center" valign="top">38</td>
<td align="left" valign="top">Bradykinesia</td>
<td align="center" valign="top">4</td>
<td align="center" valign="top">2</td>
<td align="center" valign="top">13</td>
<td align="center" valign="top">3</td>
<td align="center" valign="top">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="top"><italic>GBA</italic></td>
<td align="left" valign="top">p.A502H</td>
<td align="center" valign="top">M</td>
<td align="center" valign="top">52</td>
<td align="center" valign="top">51</td>
<td align="left" valign="top">Bradykinesia</td>
<td align="center" valign="top">1</td>
<td align="center" valign="top">2</td>
<td align="center" valign="top">22</td>
<td align="center" valign="top">20</td>
<td align="center" valign="top">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="top"><italic>GBA</italic></td>
<td align="left" valign="top">p.L483P</td>
<td align="center" valign="top">F</td>
<td align="center" valign="top">49</td>
<td align="center" valign="top">47</td>
<td align="left" valign="top">Resting tremor</td>
<td align="center" valign="top">2</td>
<td align="center" valign="top">2</td>
<td align="center" valign="top">9</td>
<td align="center" valign="top">18</td>
<td align="center" valign="top">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="top"><italic>GBA</italic></td>
<td align="left" valign="top">p.A123S</td>
<td align="center" valign="top">M</td>
<td align="center" valign="top">43</td>
<td align="center" valign="top">38</td>
<td align="left" valign="top">Resting tremor</td>
<td align="center" valign="top">5</td>
<td align="center" valign="top">2</td>
<td align="center" valign="top">39</td>
<td align="center" valign="top">38</td>
<td align="center" valign="top">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="top"><italic>LRRK2</italic></td>
<td align="left" valign="top">p. G2385R</td>
<td align="center" valign="top">M</td>
<td align="center" valign="top">64</td>
<td align="center" valign="top">59</td>
<td align="left" valign="top">Resting tremor</td>
<td align="center" valign="top">5</td>
<td align="center" valign="top">2.5</td>
<td align="center" valign="top">28</td>
<td align="center" valign="top">19</td>
<td align="center" valign="top">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="top"><italic>LRRK2</italic></td>
<td align="left" valign="top">p. G2385R</td>
<td align="center" valign="top">M</td>
<td align="center" valign="top">65</td>
<td align="center" valign="top">63</td>
<td align="left" valign="top">Bradykinesia</td>
<td align="center" valign="top">2</td>
<td align="center" valign="top">2.5</td>
<td align="center" valign="top">42</td>
<td align="center" valign="top">73</td>
<td align="center" valign="top">+</td>
</tr>
<tr>
<td align="left" valign="top"><italic>LRRK2</italic></td>
<td align="left" valign="top">p. G2385R</td>
<td align="center" valign="top">M</td>
<td align="center" valign="top">46</td>
<td align="center" valign="top">45</td>
<td align="left" valign="top">Resting tremor</td>
<td align="center" valign="top">1</td>
<td align="center" valign="top">1</td>
<td align="center" valign="top">15</td>
<td align="center" valign="top">37</td>
<td align="center" valign="top">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="top"><italic>LRRK2</italic></td>
<td align="left" valign="top">p. G2385R</td>
<td align="center" valign="top">M</td>
<td align="center" valign="top">54</td>
<td align="center" valign="top">48</td>
<td align="left" valign="top">Bradykinesia</td>
<td align="center" valign="top">6</td>
<td align="center" valign="top">3</td>
<td align="center" valign="top">64</td>
<td align="center" valign="top">73</td>
<td align="center" valign="top">+</td>
</tr>
<tr>
<td align="left" valign="top"><italic>LRRK2</italic></td>
<td align="left" valign="top">p. G2385R</td>
<td align="center" valign="top">M</td>
<td align="center" valign="top">74</td>
<td align="center" valign="top">73</td>
<td align="left" valign="top">Bradykinesia</td>
<td align="center" valign="top">1</td>
<td align="center" valign="top">2</td>
<td align="center" valign="top">23</td>
<td align="center" valign="top">34</td>
<td align="center" valign="top">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="top"><italic>LRRK2</italic></td>
<td align="left" valign="top">p. G2385R</td>
<td align="center" valign="top">F</td>
<td align="center" valign="top">65</td>
<td align="center" valign="top">61</td>
<td align="left" valign="top">Bradykinesia</td>
<td align="center" valign="top">4</td>
<td align="center" valign="top">2</td>
<td align="center" valign="top">41</td>
<td align="center" valign="top">60</td>
<td align="center" valign="top">+</td>
</tr>
<tr>
<td align="left" valign="top"><italic>LRRK2</italic></td>
<td align="left" valign="top">p. G2385R</td>
<td align="center" valign="top">M</td>
<td align="center" valign="top">75</td>
<td align="center" valign="top">71</td>
<td align="left" valign="top">Resting tremor</td>
<td align="center" valign="top">4</td>
<td align="center" valign="top">2.5</td>
<td align="center" valign="top">30</td>
<td align="center" valign="top">34</td>
<td align="center" valign="top">+</td>
</tr>
<tr>
<td align="left" valign="top"><italic>LRRK2</italic></td>
<td align="left" valign="top">p. G2385R</td>
<td align="center" valign="top">M</td>
<td align="center" valign="top">61</td>
<td align="center" valign="top">56</td>
<td align="left" valign="top">Resting tremor</td>
<td align="center" valign="top">5</td>
<td align="center" valign="top">4</td>
<td align="center" valign="top">69</td>
<td align="center" valign="top">72</td>
<td align="center" valign="top">+</td>
</tr>
<tr>
<td align="left" valign="top"><italic>LRRK2</italic></td>
<td align="left" valign="top">p. G2385R</td>
<td align="center" valign="top">F</td>
<td align="center" valign="top">58</td>
<td align="center" valign="top">43</td>
<td align="left" valign="top">Resting tremor</td>
<td align="center" valign="top">15</td>
<td align="center" valign="top">3</td>
<td align="center" valign="top">80</td>
<td align="center" valign="top">59</td>
<td align="center" valign="top">+</td>
</tr>
<tr>
<td align="left" valign="top"><italic>LRRK2</italic></td>
<td align="left" valign="top">p. G2385R</td>
<td align="center" valign="top">M</td>
<td align="center" valign="top">64</td>
<td align="center" valign="top">61</td>
<td align="left" valign="top">Resting tremor-Bradykinesia</td>
<td align="center" valign="top">3</td>
<td align="center" valign="top">2.5</td>
<td align="center" valign="top">54</td>
<td align="center" valign="top">56</td>
<td align="center" valign="top">+</td>
</tr>
<tr>
<td align="left" valign="top"><italic>LRRK2</italic></td>
<td align="left" valign="top">p. G2385R</td>
<td align="center" valign="top">F</td>
<td align="center" valign="top">63</td>
<td align="center" valign="top">59</td>
<td align="left" valign="top">Resting tremor-Bradykinesia</td>
<td align="center" valign="top">4</td>
<td align="center" valign="top">3</td>
<td align="center" valign="top">89</td>
<td align="center" valign="top">86</td>
<td align="center" valign="top">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="top"><italic>LRRK2</italic></td>
<td align="left" valign="top">p. G2385R</td>
<td align="center" valign="top">F</td>
<td align="center" valign="top">67</td>
<td align="center" valign="top">55</td>
<td align="left" valign="top">Resting tremor</td>
<td align="center" valign="top">12</td>
<td align="center" valign="top">3</td>
<td align="center" valign="top">91</td>
<td align="center" valign="top">80</td>
<td align="center" valign="top">+</td>
</tr>
<tr>
<td align="left" valign="top"><italic>LRRK2</italic></td>
<td align="left" valign="top">p. G2385R</td>
<td align="center" valign="top">F</td>
<td align="center" valign="top">60</td>
<td align="center" valign="top">45</td>
<td align="left" valign="top">Resting tremor</td>
<td align="center" valign="top">15</td>
<td align="center" valign="top">3</td>
<td align="center" valign="top">75</td>
<td align="center" valign="top">25</td>
<td align="center" valign="top">&#x2212;</td>
</tr>
<tr>
<td align="left" valign="top"><italic>LRRK2</italic></td>
<td align="left" valign="top">p. A1728H</td>
<td align="center" valign="top">F</td>
<td align="center" valign="top">50</td>
<td align="center" valign="top">47</td>
<td align="left" valign="top">Bradykinesia</td>
<td align="center" valign="top">3</td>
<td align="center" valign="top">2</td>
<td align="center" valign="top">19</td>
<td align="center" valign="top">14</td>
<td align="center" valign="top">&#x2212;</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p><italic>CHCHD2</italic>, coiled-coil-helix-coil-helix domain containing 2; <italic>RAB39B</italic>, Ras analog in brain 39b; <italic>PRKN</italic>, parkin RBR E3 ubiquitin protein ligase; <italic>LRRK2</italic>, leucine-rich repeat kinase 2; <italic>GBA</italic>, glucocerebrosidase; AAO, age at onset; MDS-UPDRS III, Movement Disorder Society Unified Parkinson&#x2019;s Disease Ranking Scale part III; NMSS, nonmotor symptoms scale; RBD, rapid eye movement sleep behavior disorder.</p>
</table-wrap-foot>
</table-wrap>
<p>The <italic>RAB39B</italic> E179fsX48 mutation was identified in a family with X-linked PD, with both patients presenting with juvenile parkinsonism. The mean AAO was 11.00&#x2009;&#x00B1;&#x2009;1.41&#x2009;years (<xref ref-type="table" rid="tab1">Table 1</xref>). Both patients exhibited major motor symptoms but mild nonmotor symptoms, while one patient exhibited moderate cognitive decline. Disease progression was extremely slow, with a mean disease duration of 32.00&#x2009;&#x00B1;&#x2009;28.28&#x2009;years (<xref ref-type="table" rid="tab1">Tables 1</xref>, <xref ref-type="table" rid="tab2">2</xref>) and both patients showed moderate responses to levodopa treatment. In addition, compound heterozygous <italic>PRKN</italic> mutations were identified in 15 unrelated patients, with a single case of homozygosity found in a patient resulting from a consanguineous marriage. These patients presented with early-onset parkinsonism and slow progression, exhibiting a mean AAO of 28.06&#x2009;&#x00B1;&#x2009;8.42&#x2009;years and mean disease duration of 9.88&#x2009;&#x00B1;&#x2009;6.53&#x2009;years (<xref ref-type="table" rid="tab1">Tables 1</xref>, <xref ref-type="table" rid="tab2">2</xref>). All 16 patients responded well to levodopa treatment, although three patients experienced dyskinesias as a side effect.</p>
<p>Thirteen unrelated patients carried the genetic risk factor <italic>LRRK2</italic> G2385R, while one harbored the A1728H mutation. These patients presented with iPD, with a mean AAO of 49.61&#x2009;&#x00B1;&#x2009;7.14&#x2009;years and mean disease duration of 7.72&#x2009;&#x00B1;&#x2009;6.39&#x2009;years (<xref ref-type="table" rid="tab1">Tables 1</xref>, <xref ref-type="table" rid="tab2">2</xref>). Twelve out of the 14 patients responded well to levodopa therapy.</p>
<p>Four out of five patients with heterozygous <italic>GBA</italic> mutations exhibited early-onset parkinsonism, with a mean AAO of 41.20&#x2009;&#x00B1;&#x2009;10.21&#x2009;years and mean disease duration of 3.40&#x2009;&#x00B1;&#x2009;2.30&#x2009;years (<xref ref-type="table" rid="tab1">Tables 1</xref>, <xref ref-type="table" rid="tab2">2</xref>). Five patients responded well to levodopa treatment, although two developed dyskinesias.</p>
</sec>
<sec id="sec17">
<title>Similar p-&#x03B1;-syn deposits in cutaneous nerve fibers in genetic PD and iPD patients</title>
<p>P-&#x03B1;-syn deposits were detected in the subepidermal plexus, dermal nerve bundles, arrector pili muscles, and blood vessels (<xref ref-type="fig" rid="fig1">Figure 1</xref>) of three PD patients with the <italic>CHCHD2</italic> T61I mutation (75%), 11 PD patients with <italic>LRRK2</italic> mutations (78.57%), and two patients with <italic>GBA</italic> mutations (40%; <xref ref-type="table" rid="tab3">Table 3</xref>). However, p-&#x03B1;-syn were not detected in PD patients with <italic>RAB39B</italic> (0%, 0/2) and <italic>PRKN</italic> (0%, 0/16) mutations.</p>
<fig position="float" id="fig1">
<label>Figure 1</label>
<caption>
<p>Immunofluorescence of different skin biopsy structures from PD patients with <italic>CHCHD2</italic>, <italic>LRRK2</italic> and <italic>GBA</italic> mutations. Phosphorylated &#x03B1;-synuclein (p-&#x03B1;-syn, green) was deposited in dermal nerve bundles, erector pili muscles, blood vessels, sweat glands, and subepidermal plexuses. PGP9.5 (red): protein-coding gene product 9.5. Scale bar&#x2009;=&#x2009;50&#x2009;&#x03BC;m.</p>
</caption>
<graphic xlink:href="fneur-15-1404492-g001.tif"/>
</fig>
<table-wrap position="float" id="tab3">
<label>Table 3</label>
<caption>
<p>Summary of differences in p-&#x03B1;-syn-positivity ratio in skin biopsies between genetic PD and iPD patients.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th/>
<th align="center" valign="top"><italic>CHCHD2</italic></th>
<th align="center" valign="top"><italic>LRRK2</italic></th>
<th align="center" valign="top"><italic>GBA</italic></th>
<th align="center" valign="top">iPD</th>
<th align="center" valign="top" colspan="3"><italic>p-</italic>value</th>
</tr>
<tr>
<th/>
<th align="center" valign="top">(<italic>n</italic>&#x2009;=&#x2009;4)</th>
<th align="center" valign="top">(<italic>n</italic>&#x2009;=&#x2009;14)</th>
<th align="center" valign="top">(<italic>n</italic>&#x2009;=&#x2009;5)</th>
<th align="center" valign="top">(<italic>n</italic>&#x2009;=&#x2009;100)</th>
<th align="center" valign="top">a</th>
<th align="center" valign="top">b</th>
<th align="center" valign="top">c</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="bottom">p-&#x03B1;-syn-positive ratio, <italic>n</italic> (%)</td>
<td align="center" valign="bottom">3 (75%)</td>
<td align="center" valign="top">11 (78.57%)</td>
<td align="center" valign="top">2 (40%)</td>
<td align="center" valign="bottom">72 (72%)</td>
<td align="center" valign="top">1.00<sup>3</sup></td>
<td align="center" valign="top">0.62<sup>2</sup></td>
<td align="center" valign="top">0.15<sup>2</sup></td>
</tr>
<tr>
<td align="left" valign="bottom">Subepidermal plexus, <italic>n</italic> (%)</td>
<td align="center" valign="bottom">2 (50%)</td>
<td align="center" valign="top">7 (50%)</td>
<td align="center" valign="top">0 (0%)</td>
<td align="center" valign="bottom">52 (52%)</td>
<td align="center" valign="top">1.00<sup>3</sup></td>
<td align="center" valign="top">0.68<sup>1</sup></td>
<td align="center" valign="top">0.06<sup>3</sup></td>
</tr>
<tr>
<td align="left" valign="bottom">Dermal bundle, <italic>n</italic> (%)</td>
<td align="center" valign="bottom">3 (75%)</td>
<td align="center" valign="top">9 (64.29%)</td>
<td align="center" valign="top">2 (40%)</td>
<td align="center" valign="bottom">65 (65%)</td>
<td align="center" valign="top">1.00<sup>2</sup></td>
<td align="center" valign="top">1.00<sup>2</sup></td>
<td align="center" valign="top">0.35<sup>2</sup></td>
</tr>
<tr>
<td align="left" valign="bottom">Sweat gland, <italic>n</italic> (%)</td>
<td align="center" valign="bottom">0 (0%)</td>
<td align="center" valign="top">0 (0%)</td>
<td align="center" valign="top">0 (0%)</td>
<td align="center" valign="bottom">9 (9%)</td>
<td align="center" valign="top">1.00<sup>3</sup></td>
<td align="center" valign="top">1.00<sup>3</sup></td>
<td align="center" valign="top">1.00<sup>3</sup></td>
</tr>
<tr>
<td align="left" valign="bottom">Arrector muscle pili, <italic>n</italic> (%)</td>
<td align="center" valign="bottom">1 (25%)</td>
<td align="center" valign="top">1 (7.14%)</td>
<td align="center" valign="top">2 (40%)</td>
<td align="center" valign="bottom">6 (6%)</td>
<td align="center" valign="top">0.19<sup>2</sup></td>
<td align="center" valign="top">0.56<sup>2</sup></td>
<td align="center" valign="top">0.26<sup>2</sup></td>
</tr>
<tr>
<td align="left" valign="bottom">Vessel, <italic>n</italic> (%)</td>
<td align="center" valign="bottom">0 (0%)</td>
<td align="center" valign="top">3 (21.43%)</td>
<td align="center" valign="top">0 (0%)</td>
<td align="center" valign="bottom">30 (30%)</td>
<td align="center" valign="top">0.55<sup>3</sup></td>
<td align="center" valign="top">0.53<sup>2</sup></td>
<td align="center" valign="top">0.55<sup>3</sup></td>
</tr>
<tr>
<td align="left" valign="bottom">Follicle <italic>n</italic> (%)</td>
<td align="center" valign="bottom">0 (0%)</td>
<td align="center" valign="top">0 (0%)</td>
<td align="center" valign="top">0 (0%)</td>
<td align="center" valign="bottom">2 (2%)</td>
<td align="center" valign="top">1.00<sup>3</sup></td>
<td align="center" valign="top">1.00<sup>3</sup></td>
<td align="center" valign="top">1.00<sup>3</sup></td>
</tr>
<tr>
<td align="left" valign="bottom">p-&#x03B1;-syn-positive in DL, <italic>n</italic> (%)</td>
<td align="center" valign="bottom">3 (75%)</td>
<td align="center" valign="top">8 (57.14%)</td>
<td align="center" valign="top">2 (40%)</td>
<td align="center" valign="bottom">52 (52%)</td>
<td align="center" valign="top">1.00<sup>2</sup></td>
<td align="center" valign="top">0.68<sup>1</sup></td>
<td align="center" valign="top">0.67<sup>2</sup></td>
</tr>
<tr>
<td align="left" valign="bottom">p-&#x03B1;-syn-positive in C7, <italic>n</italic> (%)</td>
<td align="center" valign="bottom">3 (75%)</td>
<td align="center" valign="top">9 (64.29%)</td>
<td align="center" valign="top">0 (0%)</td>
<td align="center" valign="bottom">57 (57%)</td>
<td align="center" valign="top">1.00<sup>2</sup></td>
<td align="center" valign="top">0.81<sup>1</sup></td>
<td align="center" valign="top">0.01<sup>3</sup> &#x002A;</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p><italic>P</italic>-values are shown as follows: <sup>a</sup><italic>CHCHD2</italic> vs. iPD; <sup>b</sup><italic>LRRK2</italic> vs. iPD; <sup>c</sup><italic>GBA</italic> vs. iPD. <sup>&#x002A;</sup><italic>p</italic>&#x2009;&#x003C;&#x2009;0.05. DL, distal leg. <sup>1</sup>Pearson &#x03C7;<sup>2</sup> (<italic>n</italic>&#x2009;&#x2265;&#x2009;40 and T&#x2009;&#x2265;&#x2009;5). <sup>2</sup>Continuous correction (<italic>n</italic>&#x2009;&#x2265;&#x2009;40 and 1&#x2009;&#x2264;&#x2009;T&#x2009;&#x2264;&#x2009;5). <sup>3</sup>Fisher&#x2019;s exact probabilities (<italic>n</italic>&#x2009;&#x003C;&#x2009;40 or T&#x2009;&#x003C;&#x2009;1).</p>
</table-wrap-foot>
</table-wrap>
<p>Further analysis of p-&#x03B1;-syn deposition in the 100 iPD patients and 20 healthy controls revealed that p-&#x03B1;-syn was deposited in 72/100 (72%) iPD patients (<xref ref-type="table" rid="tab3">Table 3</xref>) but not in any of the healthy controls. Furthermore, p-&#x03B1;-syn-positive nerve fibers were found in the subepidermal plexus, dermal nerve bundles, arrector pili muscles, sweat glands, and blood vessels (<xref ref-type="fig" rid="fig2">Figure 2</xref>).</p>
<fig position="float" id="fig2">
<label>Figure 2</label>
<caption>
<p>Immunofluorescence staining of different skin biopsy structures from iPD patients and healthy controls. Phosphorylated &#x03B1;-synuclein (p-&#x03B1;-syn, green) was deposited in subepidermal plexus, dermal nerve bundle, erector pili muscle, sweat gland, and blood vessels. PGP9.5 (red): protein-coding gene product 9.5. Scale bar&#x2009;=&#x2009;50&#x2009;&#x03BC;m.</p>
</caption>
<graphic xlink:href="fneur-15-1404492-g002.tif"/>
</fig>
<p>The somatosensory nerve antibody CGRP, sympathetic nerve antibody TH, and parasympathetic nerve antibody VIP were used to identify p-&#x03B1;-syn-positive structures. Results showed that CGRP was positive in the subepidermal plexus (<xref ref-type="fig" rid="fig3">Figure 3</xref>) and some superficial dermal nerve bundles. TH was positive in the arrector pili muscles, sweat glands, blood vessels (<xref ref-type="fig" rid="fig3">Figure 3</xref>), and some deep dermal nerve bundles. VIP was positive in the sudomotor fibers and some deep dermal nerve bundles (<xref ref-type="fig" rid="fig3">Figure 3</xref>).</p>
<fig position="float" id="fig3">
<label>Figure 3</label>
<caption>
<p>Immunofluorescence staining of somatosensory and autonomic nerve structures of PD patients. Somatosensory nerve antibody calcitonin gene-related peptide (CGRP, red) was double-stained in subepidermal plexus, sympathetic nerve antibody tyrosine hydroxylase (TH, red) was positive in blood vessels, and parasympathetic nerve antibody vasoactive intestinal peptide (VIP, red) was double-stained in dermal nerve bundles. Phosphorylated &#x03B1;-synuclein (p-&#x03B1;-syn, green). Scale bar&#x2009;=&#x2009;50&#x2009;&#x03BC;m.</p>
</caption>
<graphic xlink:href="fneur-15-1404492-g003.tif"/>
</fig>
</sec>
<sec id="sec18">
<title>Similar p-&#x03B1;-syn deposition rates and sites in skin biopsies from genetic PD and iPD patients</title>
<p>The total p-&#x03B1;-syn-positive ratios were 3/4 (75%) in the <italic>CHCHD2</italic> group, 11/14 (78.57%) in the <italic>LRRK2</italic> group, 2/5 (40%) in the <italic>GBA</italic> group, and 72/100 (72%) in the iPD group. No significant differences in skin p-&#x03B1;-syn-positive deposition were observed among the <italic>CHCHD2</italic>, <italic>LRRK2</italic>, <italic>GBA</italic>, and iPD patients (<italic>p</italic>&#x2009;=&#x2009;1.00, <italic>p</italic>&#x2009;=&#x2009;0.62, <italic>p</italic>&#x2009;=&#x2009;0.15; <xref ref-type="table" rid="tab3">Table 3</xref>). The skin biopsy innervation structures included the subepidermal plexus, dermal nerve bundles, arrector pili muscles, sweat glands, blood vessels, and follicles. The p-&#x03B1;-syn-positive ratios for the subepidermal plexus were 2/4 (50%) in the <italic>CHCHD2</italic> group, 7/14 (50%) in the <italic>LRRK2</italic> group, and 52/100 (52%) in the iPD group (<italic>p</italic>&#x2009;=&#x2009;1.00, <italic>p</italic>&#x2009;=&#x2009;1.00). The p-&#x03B1;-syn-positive ratios for the dermal nerve bundles were 3/4 (75%) in the <italic>CHCHD2</italic> group, 9/14 (64.29%) in the <italic>LRRK2</italic> group, 2/5 (40%) in the <italic>GBA</italic> group, and 65/100 (65%) in the iPD group (<italic>p</italic>&#x2009;=&#x2009;1.00, <italic>p</italic>&#x2009;=&#x2009;1.00 and <italic>p</italic>&#x2009;=&#x2009;0.35). The p-&#x03B1;-syn-positive ratios for the arrector pili muscles were 1/4 (25%) in the <italic>CHCHD2</italic> group, 1/12 (7.14%) in the <italic>LRRK2</italic> group, 2/5 (40%) in the <italic>GBA</italic> group, and 6/100 (6%) in the iPD group (<italic>p</italic>&#x2009;=&#x2009;0.19, <italic>p</italic>&#x2009;=&#x2009;0.56 and <italic>p</italic>&#x2009;=&#x2009;0.26). No significant differences in p-&#x03B1;-syn-positive deposition were found in the different skin biopsy innervation structures between the genetic PD and iPD patients (<xref ref-type="table" rid="tab3">Table 3</xref>).</p>
<p>The p-&#x03B1;-syn-positive percentages were 3/4 (75%) in the DL and C7 of the <italic>CHCHD2</italic> group, 8/14 (57.14%) in the DL and 9/14 (64.29%) in the C7 of the <italic>LRRK2</italic> group, 2/5 (40%) in the DL of the <italic>GBA</italic> group, and 52/100 (52%) in the DL and 57/100 (57%) in the C7 of the iPD group. While no significant differences were observed in the percentage of p-&#x03B1;-syn-positive cells in the DL (<italic>p</italic>&#x2009;=&#x2009;1.00, <italic>p</italic>&#x2009;=&#x2009;0.68, and <italic>p</italic>&#x2009;=&#x2009;0.67), significant differences were found between the <italic>GBA</italic> and iPD groups in the C7 (<italic>p</italic>&#x2009;=&#x2009;0.01; <xref ref-type="table" rid="tab3">Table 3</xref>).</p>
</sec>
<sec id="sec19">
<title>Skin biopsy and brain autopsy synucleinopathy results from our data and literature review data were highly consistent with those of genetic PD patients</title>
<p>We examined 41 skin biopsies from genetic PD patients (<italic>CHCHD2</italic>, <italic>n</italic>&#x2009;=&#x2009;4; <italic>RAB39B</italic>, <italic>n</italic>&#x2009;=&#x2009;2; <italic>GBA</italic>, <italic>n</italic>&#x2009;=&#x2009;5; <italic>PRKN</italic>, <italic>n</italic>&#x2009;=&#x2009;16; and <italic>LRRK2</italic>, <italic>n</italic>&#x2009;=&#x2009;14) and retrieved 64 skin biopsy and 205 brain autopsy genetic PD patients from the literature review (<xref ref-type="table" rid="tab4">Table 4</xref>). The skin biopsy synucleinopathies of the <italic>CHCHD2</italic>, <italic>RAB39B</italic>, <italic>LRRK2</italic>, and <italic>GBA</italic> groups were the same as the brain autopsy synucleinopathies. However, there was a significant difference in synucleinopathies between the PRKN-related PD patients and brain autopsies (<xref ref-type="table" rid="tab4">Table 4</xref>).</p>
<table-wrap position="float" id="tab4">
<label>Table 4</label>
<caption>
<p>Summary of &#x03B1;-syn deposition rate in skin biopsies and brain autopsies of genetic PD patients.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left" valign="top" rowspan="2">Gene</th>
<th align="center" valign="top" colspan="2">Skin biopsy</th>
<th align="center" valign="top">Autopsy</th>
<th align="center" valign="top" rowspan="2"><italic>P</italic>-value</th>
</tr>
<tr>
<th align="center" valign="top">(Our data <italic>n</italic>&#x2009;=&#x2009;41)</th>
<th align="center" valign="top">(Data from literature <italic>n</italic>&#x2009;=&#x2009;64)</th>
<th align="center" valign="top">(Data from literature <italic>n</italic>&#x2009;=&#x2009;205)</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="top"><italic>CHCHD2</italic></td>
<td align="center" valign="top">75% (3/4)</td>
<td align="center" valign="top">/</td>
<td align="center" valign="top">100% (1/1)</td>
<td align="center" valign="top">1.00<sup>3</sup></td>
</tr>
<tr>
<td align="left" valign="top"><italic>RAB39B</italic></td>
<td align="center" valign="top">0% (0/2)</td>
<td align="center" valign="top">/</td>
<td align="center" valign="top">100% (1/1)</td>
<td align="center" valign="top">0.33<sup>3</sup></td>
</tr>
<tr>
<td align="left" valign="top"><italic>LRRK2</italic></td>
<td align="center" valign="top">78.57% (11/14)</td>
<td align="center" valign="top">100% (7/7)</td>
<td align="center" valign="top">64.4% (38/59)</td>
<td align="center" valign="top">0.10<sup>2</sup></td>
</tr>
<tr>
<td align="left" valign="top"><italic>PRKN</italic></td>
<td align="center" valign="top">0% (0/16)</td>
<td align="center" valign="top">0% (0/20)</td>
<td align="center" valign="top">55% (11/20)</td>
<td align="center" valign="top">&#x003C;0.0001<sup>3&#x002A;</sup></td>
</tr>
<tr>
<td align="left" valign="top"><italic>GBA</italic></td>
<td align="center" valign="top">40% (2/5)</td>
<td align="center" valign="top">64% (16/25)</td>
<td align="center" valign="top">96% (92/96)</td>
<td align="center" valign="top">0.10<sup>1</sup></td>
</tr>
<tr>
<td align="left" valign="top"><italic>SNCA</italic></td>
<td align="center" valign="top">/</td>
<td align="center" valign="top">100% (10/10)</td>
<td align="center" valign="top">100% (27/27)</td>
<td align="center" valign="top">1.00<sup>3</sup></td>
</tr>
<tr>
<td align="left" valign="top"><italic>DJ-1</italic></td>
<td align="center" valign="top">/</td>
<td align="center" valign="top">100% (2/2)</td>
<td align="center" valign="top">100% (1/1)</td>
<td align="center" valign="top">1.00<sup>3</sup></td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p><sup>1</sup>Pearson &#x03C7;<sup>2</sup> (<italic>n</italic>&#x2009;&#x2265;&#x2009;40 and T&#x2009;&#x2265;&#x2009;5); <sup>2</sup>Continuous correction (<italic>n</italic>&#x2009;&#x2265;&#x2009;40 and 1&#x2009;&#x2264;&#x2009;T&#x2009;&#x2264;&#x2009;5); <sup>3</sup>Fisher&#x2019;s exact probabilities (<italic>n</italic>&#x2009;&#x003C;&#x2009;40 or T&#x2009;&#x003C;&#x2009;1). <sup>&#x002A;</sup><italic>p</italic>&#x2009;&#x003C;&#x2009;0.05.</p>
</table-wrap-foot>
</table-wrap>
<p>The detailed skin biopsy and brain autopsy synucleinopathy results for the genetic PD patients are shown in <xref ref-type="table" rid="tab5">Table 5</xref>. Mendelian inheritance includes autosomal dominant (AD), autosomal recessive (AR), X-linked dominant (XD), and X-linked recessive inheritance (XR). Here, <italic>CHCHD2</italic>, <italic>LRRK2</italic>, and <italic>GBA</italic> were recognized as AD-PD-related genes. Skin biopsies from one family with the <italic>CHCHD2</italic> T61I mutation were positive for p-&#x03B1;-syn deposits. One brain autopsy patient with the <italic>CHCHD2</italic> T61I mutation showed p-&#x03B1;-syn-positive deposits, including diffuse Lewy bodies (LBs) and Lewy neurites (LNs). Eleven out of 14 <italic>LRRK2</italic> mutation carriers contained p-&#x03B1;-syn-positive deposits in their skin biopsies. Based on our literature review, <italic>LRRK2</italic> G2019S/R1441G/R1441C mutations were also found in European and North American individuals with p-&#x03B1;-syn-positive deposition in skin biopsies and brain autopsies. Two out of the five <italic>GBA</italic> mutation carriers contained p-&#x03B1;-syn-positive deposits in their skin biopsies. The autopsy <italic>GBA</italic> mutation sites were primarily distributed in Europe and North America. Notably, p-&#x03B1;-syn depositions were positive in skin biopsies and brain autopsy samples in patients harboring <italic>GBA</italic> mutations.</p>
<table-wrap position="float" id="tab5">
<label>Table 5</label>
<caption>
<p>Summary of observed &#x03B1;-syn deposition in skin biopsies and brain autopsies of patients with genetic PD.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left" valign="top" rowspan="2">Gene</th>
<th align="center" valign="top" rowspan="2">Mode of inheritance</th>
<th align="center" valign="top" colspan="3">Skin biopsy</th>
<th align="center" valign="top" colspan="3">Autopsy</th>
</tr>
<tr>
<th align="left" valign="top">Mutation sites</th>
<th align="left" valign="top">Ethnicity</th>
<th align="left" valign="top">&#x03B1;-syn deposition</th>
<th align="left" valign="top">Mutation sites</th>
<th align="left" valign="top">Ethnicity</th>
<th align="left" valign="top">&#x03B1;-syn deposition</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="top"><italic>CHCHD2</italic></td>
<td align="center" valign="top">AD</td>
<td align="left" valign="top">T61I (our data)</td>
<td align="char" valign="top" char="&#x00D7;">Asian</td>
<td align="left" valign="top">p-&#x03B1;-syn (+)</td>
<td align="left" valign="top">T61I (<xref ref-type="bibr" rid="ref16">16</xref>)</td>
<td align="char" valign="top" char="&#x00D7;">Asian</td>
<td align="left" valign="top">p-&#x03B1;-syn (+)</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="2"><italic>LRRK2</italic></td>
<td align="center" valign="top" rowspan="2">AD</td>
<td align="left" valign="top">G2385R; A1728H (our data); G2019S (<xref ref-type="bibr" rid="ref30">30</xref>)</td>
<td align="left" valign="top" rowspan="2">Asian; North American</td>
<td align="left" valign="top" rowspan="2">p-&#x03B1;-syn (+)</td>
<td align="left" valign="top" rowspan="2">G2019S; (<xref ref-type="bibr" rid="ref1">1</xref>, <xref ref-type="bibr" rid="ref3">3</xref>, <xref ref-type="bibr" rid="ref31 ref32 ref33 ref34 ref35">31&#x2013;35</xref>) R1441G; (<xref ref-type="bibr" rid="ref36">36</xref>) R1441C; (<xref ref-type="bibr" rid="ref37">37</xref>); others; (<xref ref-type="bibr" rid="ref38">38</xref>, <xref ref-type="bibr" rid="ref39">39</xref>)</td>
<td align="left" valign="top" rowspan="2">European; North American</td>
<td align="left" valign="top" rowspan="2">p-&#x03B1;-syn (+)</td>
</tr>
<tr>
<td align="char" valign="top" char="&#x00D7;">G2019S, R1441G (<xref ref-type="bibr" rid="ref30">30</xref>)</td>
</tr>
<tr>
<td align="left" valign="top"><italic>SNCA</italic></td>
<td align="center" valign="top">AD</td>
<td align="left" valign="top">E46K; (<xref ref-type="bibr" rid="ref8">8</xref>) A53T; Duplication (<xref ref-type="bibr" rid="ref30">30</xref>)</td>
<td align="left" valign="top">European; North American</td>
<td align="left" valign="top">p-&#x03B1;-syn (+)</td>
<td align="left" valign="top">E46K; (<xref ref-type="bibr" rid="ref40">40</xref>) A53T; (<xref ref-type="bibr" rid="ref41 ref42 ref43 ref44">41&#x2013;44</xref>) Duplication; (<xref ref-type="bibr" rid="ref45 ref46 ref47 ref48 ref49">45&#x2013;49</xref>) A30P; (<xref ref-type="bibr" rid="ref50">50</xref>) others (<xref ref-type="bibr" rid="ref49">49</xref>, <xref ref-type="bibr" rid="ref51">51</xref>)</td>
<td align="left" valign="top">European; North American</td>
<td align="left" valign="top">Alpha-syn (+)</td>
</tr>
<tr>
<td align="left" valign="top"><italic>GBA</italic></td>
<td align="center" valign="top">AD</td>
<td align="left" valign="top">L483P; A502C; A502H; A123S (our data); N370S; E326K; L444P; (<xref ref-type="bibr" rid="ref10">10</xref>) N409S; L483P; N409S homo (<xref ref-type="bibr" rid="ref30">30</xref>)</td>
<td align="left" valign="top">Asian; European; North American</td>
<td align="left" valign="top">p-&#x03B1;-syn (+)</td>
<td align="left" valign="top">N370S; E326K; L444P; D409H; R496H; N370S homo; et al. (<xref ref-type="bibr" rid="ref4">4</xref>, <xref ref-type="bibr" rid="ref5">5</xref>, <xref ref-type="bibr" rid="ref52 ref53 ref54 ref55 ref56 ref57 ref58 ref59 ref60 ref61">52&#x2013;61</xref>)</td>
<td align="left" valign="top">European; North American</td>
<td align="left" valign="top">Alpha-syn (+)</td>
</tr>
<tr>
<td align="left" valign="top"><italic>DJ-1</italic></td>
<td align="center" valign="top">AR</td>
<td align="left" valign="top">E4 del; A36Cfs&#x002A;12 (<xref ref-type="bibr" rid="ref12">12</xref>) E3 del, A35Cfs&#x002A;12 (<xref ref-type="bibr" rid="ref30">30</xref>)</td>
<td align="left" valign="top">North American</td>
<td align="left" valign="top">Alpha-syn (+)</td>
<td align="left" valign="top">L172Q homo (<xref ref-type="bibr" rid="ref62">62</xref>)</td>
<td align="left" valign="top">European</td>
<td align="left" valign="top">Alpha-syn (+)</td>
</tr>
<tr>
<td align="left" valign="top"><italic>PRKN</italic></td>
<td align="center" valign="top">AR</td>
<td align="left" valign="top">E4 del, G284R; E3-4 del, G284R; E6-7 del, E309&#x002A;; E2-3 del, c.2T&#x003E;C; E3 del, E6 del; E3 del, E7 del; E3 del, E5 del; E3 del, c. 1310delC; E2-4 dup; c.933+5G&#x003E;T homo; p.S223&#x002A;, E2 del; E3 del, E4 del; S286 Profs&#x002A;12, E3 dup; E3-4 del, E7 del; splice-3, E3-4 del; E5-6 dup, c.2T&#x003E;C (Above all our data) R275 W, E3-4 del; c.7+5G&#x003E;T, E3-4 del; p. Asn52fs homo; E3 del, E3-4 del; (<xref ref-type="bibr" rid="ref30">30</xref>) E7 del, V56E (<xref ref-type="bibr" rid="ref12">12</xref>, <xref ref-type="bibr" rid="ref30">30</xref>); E2 del, E5 del (<xref ref-type="bibr" rid="ref11">11</xref>); E11 del, G429D; T415N homo (<xref ref-type="bibr" rid="ref12">12</xref>, <xref ref-type="bibr" rid="ref30">30</xref>)</td>
<td align="left" valign="top">Asian; North American; European</td>
<td align="left" valign="top">p-&#x03B1;-syn (&#x2212;)</td>
<td align="left" valign="top">R275W (<xref ref-type="bibr" rid="ref63 ref64 ref65">63&#x2013;65</xref>); R275 W, E6 del; R275 W, G430 W; R275 W, Pro113fs; G430D, Pro113fs; (<xref ref-type="bibr" rid="ref66">66</xref>); E7 del, 1,072&#x2009;T del (<xref ref-type="bibr" rid="ref6">6</xref>); E3 del homo (<xref ref-type="bibr" rid="ref67">67</xref>); E2-4 del homo (<xref ref-type="bibr" rid="ref7">7</xref>); E2-4 dup, E3-4 del; E4 del homo; E6-7 dup homo; E10-11 dup homo; C431F homo; C431F, E2-4 dup; E2 trip, E2-3 del; (<xref ref-type="bibr" rid="ref68">68</xref>)</td>
<td align="left" valign="top">European; North American; Asian</td>
<td align="left" valign="top">p-&#x03B1;-syn (+)</td>
</tr>
<tr>
<td align="left" valign="top"><italic>RAB39B</italic></td>
<td align="center" valign="top">XD</td>
<td align="left" valign="top">E179fsX48 (our data)</td>
<td align="left" valign="top">Asian</td>
<td align="left" valign="top">p-&#x03B1;-syn (&#x2212;)</td>
<td align="left" valign="top">T168K (<xref ref-type="bibr" rid="ref17">17</xref>)</td>
<td align="left" valign="top">Australian</td>
<td align="left" valign="top">Alpha-syn (+)</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p>Red Mutation sites from skin biopsies were obtained in our study, while the remaining skin biopsy and autopsy data were acquired from literature review.</p>
</table-wrap-foot>
</table-wrap>
<p>The <italic>PRKN</italic> gene is associated with AR-PD. In this study, we identified 15 PD patients with compound heterozygous <italic>PRKN</italic> mutation and one patient with homozygous <italic>PRKN</italic> mutation. Based on a review of the literature on skin biopsies literature, we retrieved 18 compound heterozygous <italic>PRKN</italic> mutations in North American and European PD patients. Skin biopsies from all 34 patients with <italic>PRKN</italic> mutations were negative for p-&#x03B1;-syn deposits. Furthermore, a review of autopsy literature identified 20 patients with either homozygous or compound heterozygous <italic>PRKN</italic> mutations, mostly from Europe and North America. Although the <italic>PRKN</italic> mutation sites differed between skin biopsy and brain autopsy samples, 55% (11/20, no Asian patients) of brain autopsies showed &#x03B1;-syn-positive deposition.</p>
<p>One PD family with the <italic>RAB39B</italic> E179fsX48 mutation, which exhibited XD inheritance, was sampled. The skin biopsies of both patients were negative for p-&#x03B1;-syn deposition. However, brain autopsy samples of an Australian PD patient carrying the <italic>RAB39B</italic> T168K mutation revealed p-&#x03B1;-syn-positive deposits in the SN and cortex.</p>
</sec>
<sec id="sec20">
<title>Co-neuropathology in skin biopsy of genetic PD and iPD patients</title>
<p>Co-neuropathology analysis of skin biopsies from patients with genetic PD and iPD was also performed. Immunofluorescence staining revealed aggregated &#x03B1;-syn (5G4 and ASyO5, green) deposits in dermal nerve bundles, blood vessels, sweat glands, and erector pili muscles (<xref ref-type="fig" rid="fig4">Figure 4A</xref>, from left to right). Tauopathies (AT8 and HT7, green) were deposited in the subepidermal plexus, dermal nerve bundles, sweat glands, and blood vessels (<xref ref-type="fig" rid="fig4">Figure 4A</xref>). TAR DNA-binding protein 43 (TDP-43, green) was deposited in erector pili muscles and sweat glands (<xref ref-type="fig" rid="fig4">Figure 4A</xref>).</p>
<fig position="float" id="fig4">
<label>Figure 4</label>
<caption>
<p>Co-neuropathology in patients with genetic PD and iPD. <bold>(A)</bold> Immunofluorescence staining results. Aggregated &#x03B1;-syn (5G4, green) was deposited in dermal nerve bundles, blood vessels, sweat glands, and erector pili muscles. Oligomer-specific &#x03B1;-syn (ASyO5, green) was deposited in dermal nerve bundles, blood vessels, sweat glands, and erector pili muscles. Phosphorylated tau (AT8, green) was deposited in subepidermal plexus, dermal nerve bundle, sweat glands, and blood vessels. Tau (HT7, green) was deposited in subepidermal plexus, dermal nerve bundles, sweat glands, and blood vessels. TAR DNA-binding protein 43 (TDP-43, green) was deposited in erector pili muscles and sweat glands. PGP9.5 (red): protein-coding gene product 9.5. Scale bar&#x2009;=&#x2009;50&#x2009;&#x03BC;m. <bold>(B)</bold> Heatmap results of co-neuropathology. Red indicates positive deposition, green indicates negative deposition. P-&#x03B1;-syn, &#x03B1;-syn, ASyO5, 5G4 indicate synucleinopathy, HT7, AT8 indicate tauopathy, and A&#x03B2;40 and A&#x03B2;42 indicate amyloid pathology. Other pathology contains TDP-43 and ubiquitin. Genetic PD patients and iPD patients exhibited heterogeneous co-neuropathology.</p>
</caption>
<graphic xlink:href="fneur-15-1404492-g004.tif"/>
</fig>
<p>Patients carrying <italic>LRRK2</italic>, <italic>CHCHD2</italic>, and <italic>GBA</italic> mutations, as well as those with iPD, displayed similar co-neuropathologies, including positivity for p-&#x03B1;-syn, &#x03B1;-syn, ASyO5, 5G4 (synucleinopathy), and HT7 and AT8 (p-tauopathy). PD patients with <italic>PRKN</italic> and <italic>RAB39B</italic> mutations commonly exhibited &#x03B1;-syn (synucleinopathy) and AT8 (p-tau) positivity. PD patients with <italic>LRRK2</italic> and <italic>PRKN</italic> mutations also exhibited TDP-43 and ubiquitin positivity (<xref ref-type="fig" rid="fig4">Figure 4B</xref>).</p>
</sec>
<sec id="sec21">
<title>Cutaneous &#x03B1;-synuclein exhibited prion-like activity in genetic PD and iPD</title>
<p>The &#x03B1;-syn RT-QuIC curves of iPD patients (<xref ref-type="fig" rid="fig5">Figures 5A</xref>&#x2013;<xref ref-type="fig" rid="fig5">C</xref>), PD patients with <italic>LRRK2</italic> G2385R mutations (<xref ref-type="fig" rid="fig5">Figures 5D</xref>&#x2013;<xref ref-type="fig" rid="fig5">F</xref>), PD patients with <italic>GBA</italic> mutations (<xref ref-type="fig" rid="fig5">Figures 5G</xref>&#x2013;<xref ref-type="fig" rid="fig5">I</xref>), and healthy control subjects (<xref ref-type="fig" rid="fig5">Figures 5J</xref>&#x2013;<xref ref-type="fig" rid="fig5">L</xref>) are shown. Three iPD patients (<xref ref-type="fig" rid="fig5">Figures 5A</xref>&#x2013;<xref ref-type="fig" rid="fig5">C</xref>), including one with the <italic>LRRK2</italic> G2385R mutation (<xref ref-type="fig" rid="fig5">Figure 5D</xref>) and one with the <italic>GBA</italic> A502H mutation (<xref ref-type="fig" rid="fig5">Figure 5G</xref>), exhibited RT-QuIC-positive curves. As shown in <xref ref-type="table" rid="tab6">Table 6</xref>, &#x03B1;-syn RT-QuIC can identify iPD-, <italic>LRRK2-</italic>, and <italic>GBA</italic>-positive synucleinopathies with 100% sensitivity and 100% specificity in skin biopsies.</p>
<fig position="float" id="fig5">
<label>Figure 5</label>
<caption>
<p>SAA curves of patients with genetic PD and iPD. &#x03B1;-Synuclein SAA curves of three idiopathic PD patients <bold>(A&#x2013;C)</bold>, three <italic>LRRK2</italic> G2385R mutation patients <bold>(D&#x2013;F)</bold>, three <italic>GBA</italic> mutation patients <bold>(G&#x2013;I)</bold> and three healthy controls <bold>(J&#x2013;L)</bold>. The red and blue lines shown in each figure represent replicates from the same subject.</p>
</caption>
<graphic xlink:href="fneur-15-1404492-g005.tif"/>
</fig>
<table-wrap position="float" id="tab6">
<label>Table 6</label>
<caption>
<p>&#x03B1;-Syn SAA diagnostic values in skin biopsies from patients with genetic PD.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th/>
<th align="center" valign="top"><italic>N</italic></th>
<th align="center" valign="top">SAA positive</th>
<th align="center" valign="top">Sensitivity</th>
<th align="center" valign="top">Specificity</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="bottom"><italic>LRRK2</italic> p-syn-positive</td>
<td align="center" valign="bottom">1</td>
<td align="center" valign="top">1/1</td>
<td align="center" valign="top">100%</td>
<td/>
</tr>
<tr>
<td align="left" valign="bottom"><italic>LRRK2</italic> p-syn-negative</td>
<td align="center" valign="bottom">2</td>
<td align="center" valign="top">0/2</td>
<td/>
<td align="center" valign="top">100%</td>
</tr>
<tr>
<td align="left" valign="bottom"><italic>GBA</italic> p-syn-positive</td>
<td align="center" valign="bottom">1</td>
<td align="center" valign="top">1/1</td>
<td align="center" valign="top">100%</td>
<td/>
</tr>
<tr>
<td align="left" valign="bottom"><italic>GBA</italic> p-syn-negative</td>
<td align="center" valign="bottom">3</td>
<td align="center" valign="top">0/3</td>
<td/>
<td align="center" valign="top">100%</td>
</tr>
<tr>
<td align="left" valign="bottom">iPD p-syn-positive</td>
<td align="center" valign="bottom">10</td>
<td align="center" valign="top">10/10</td>
<td align="center" valign="top">100%</td>
<td/>
</tr>
<tr>
<td align="left" valign="bottom">iPD p-syn-negative</td>
<td align="center" valign="bottom">2</td>
<td align="center" valign="top">0/2</td>
<td/>
<td align="center" valign="top">100%</td>
</tr>
</tbody>
</table>
</table-wrap>
</sec>
</sec>
<sec sec-type="discussion" id="sec22">
<title>Discussion</title>
<p>Peripheral &#x03B1;-syn is considered a promising biomarker for PD diagnosis (<xref ref-type="bibr" rid="ref9">9</xref>, <xref ref-type="bibr" rid="ref13">13</xref>, <xref ref-type="bibr" rid="ref69">69</xref>, <xref ref-type="bibr" rid="ref70">70</xref>), impacting peripheral tissues such as the skin, salivary glands, and gastrointestinal (GI) tract (<xref ref-type="bibr" rid="ref71 ref72 ref73 ref74">71&#x2013;74</xref>). Recent research, however, has detected &#x03B1;-syn and p-&#x03B1;-syn immunoreactivity in the GI tract of both PD patients and healthy controls, indicating potential concerns related to the specificity of &#x03B1;-syn deposition (<xref ref-type="bibr" rid="ref75">75</xref>). Various issues, such as low biopsy yield, invasive procedures (<xref ref-type="bibr" rid="ref76">76</xref>), and low sensitivity and specificity, may also limit the practical feasibility and clinical applicability of such tissues (<xref ref-type="bibr" rid="ref74">74</xref>). In contrast, skin biopsies offer a viable diagnostic alternative due to their simplicity, cost-effectiveness, minimally invasive nature, and high specificity and sensitivity (<xref ref-type="bibr" rid="ref9">9</xref>, <xref ref-type="bibr" rid="ref20">20</xref>). Liu et al. (<xref ref-type="bibr" rid="ref77">77</xref>) demonstrated a specificity of 100% and sensitivity of 83.3% for the diagnosis of PD based on immunofluorescence analysis of 50-&#x03BC;m skin punch biopsies. Similarly, our research achieved a specificity of 100% and sensitivity of 72%, in alignment with the above studies. The morphological characteristics of p-&#x03B1;-syn deposits in the skin are similar to those of Lewy neurites found in the brain (<xref ref-type="bibr" rid="ref69">69</xref>), underscoring the specificity and potential of skin biopsies in the identification of PD.</p>
<p>Similar cutaneous synucleinopathies have recently been detected in several PD patients with common genetic risk factors, including <italic>SNCA</italic>, <italic>DJ-1</italic>, <italic>GBA</italic>, and <italic>LRRK2</italic> (<xref ref-type="bibr" rid="ref8">8</xref>, <xref ref-type="bibr" rid="ref10 ref11 ref12 ref13">10&#x2013;13</xref>). To date, however, no premortem neuropathological studies on <italic>CHCHD2</italic> and <italic>RAB39B</italic> mutations have been reported. In this study, we identified p-&#x03B1;-syn deposits in the skin nerve of a PD patient with the <italic>CHCHD2</italic> T61I mutation. Thus, we propose that cutaneous synucleinopathies are highly similar between PD patients with <italic>CHCHD2</italic> T61I mutations and those with iPD. As expected, p-&#x03B1;-syn was found predominantly in the cutaneous autonomic structures of the study patients. According to previous reports, increased &#x03B1;-syn deposition is associated with increased autonomic dysfunction, which may explain the symptoms of autonomic nerve dysfunction in patients carrying the <italic>CHCHD2</italic> T61I mutation (<xref ref-type="bibr" rid="ref78">78</xref>). Recent brain autopsy of a PD patient with the <italic>CHCHD2</italic> T61I mutation revealed widespread Lewy pathology based on anti-p-&#x03B1;-syn immunostaining, including diffuse LBs and LNs (<xref ref-type="bibr" rid="ref16">16</xref>). Thus, these results indicate that peripheral cutaneous synucleinopathy is consistent with brain autopsy pathology in PD patients harboring the <italic>CHCHD2</italic> T61I mutation.</p>
<p>At present, the role of <italic>RAB39B</italic> in PD remains poorly understood. In the current study, p-&#x03B1;-syn deposition was not detected in the skin nerve fibers of PD patients carrying the <italic>RAB39B</italic> E179fsX48 mutation. Nonetheless, neuropathological features of PD, including neuronal loss and Lewy pathology in the SN and cortex, have been reported in PD patients with the <italic>RAB39B</italic> T168K mutation (<xref ref-type="bibr" rid="ref17">17</xref>, <xref ref-type="bibr" rid="ref18">18</xref>). A recent theoretical framework suggests two PD progression models: a &#x201C;brain-first&#x201D; scenario where initial pathological &#x03B1;-syn emergence occurs within the central nervous system, starting from the SNpc and spreading through interconnected structures to the autonomic nervous system; and a &#x201C;body-first&#x201D; scenario where pathological &#x03B1;-syn begins in the enteric nervous system, then advances caudo-rostrally to the autonomic and central nervous systems (<xref ref-type="bibr" rid="ref79">79</xref>, <xref ref-type="bibr" rid="ref80">80</xref>). In this study, brain autopsy findings from PD patients with <italic>RAB39B</italic> mutations revealed &#x03B1;-syn deposition in the SNpc and cortex but not in skin biopsies. Thus, we propose that PD patients with <italic>RAB39B</italic> mutations may predominantly exhibit a &#x201C;brain-first&#x201D; progression pattern.</p>
<p>Skin biopsies can yield insights into peripheral pathologies; yet the degree to which these observations accurately reflect intracranial pathologies requires further research, with few relevant reports on this topic. In this study, we compared synucleinopathy characteristics across genetic PD patients identified via skin biopsies and brain autopsies, considering mode of inheritance, genotype, ethnicity, and &#x03B1;-syn deposition. Notably, &#x03B1;-syn deposition was present in all skin biopsies and brain autopsies of AD-PD cases (involving <italic>CHCHD2</italic>, <italic>LRRK2</italic>, <italic>SNCA</italic>, and <italic>GBA</italic> mutations), suggesting a concordance between cutaneous and brain synucleinopathies in AD-PD patients. For AR-PD patients, &#x03B1;-syn deposition was observed in both skin biopsies and brain autopsies in <italic>DJ-1</italic>-mutant PD patients, whereas synucleinopathy was observed only in brain autopsies in <italic>PRKN</italic>-mutant PD patients. This discrepancy in the incidence of AR-PD may be linked to <italic>PRKN</italic> mutations leading to nigral degeneration without Lewy pathology (<xref ref-type="bibr" rid="ref63">63</xref>, <xref ref-type="bibr" rid="ref68">68</xref>, <xref ref-type="bibr" rid="ref81">81</xref>), a pattern confirmed by our skin biopsy results from 16 <italic>PRKN</italic> mutation carriers. However, despite the absence of Lewy pathology, synucleinopathies have still been observed in brain autopsies of older PD patients with <italic>PRKN</italic> mutations (<xref ref-type="bibr" rid="ref6">6</xref>, <xref ref-type="bibr" rid="ref7">7</xref>, <xref ref-type="bibr" rid="ref63 ref64 ref65">63&#x2013;65</xref>). Several hypotheses have been posited to explain synucleinopathy in PRKN-associated PD, including: (i) a gradual accumulation of &#x03B1;-syn with aging in these patients; (ii) a diminished capacity in late-onset PD patients to clear accumulated proteins; and (iii) the possibility that mutations result in only a partial loss of function in the PRKN ubiquitin E3 ligase (<xref ref-type="bibr" rid="ref63">63</xref>). Consequently, the presence of cutaneous synucleinopathy aligns closely with brainstem synucleinopathy in genetic PD, particularly among AD-PD cases.</p>
<p>Each gene encompasses multiple genotypes, with various mutation sites influencing functional outcomes and behavior of downstream proteins, leading to diverse phenotypes. In this study, identical mutation sites in <italic>CHCHD2</italic> (T61I) (<xref ref-type="bibr" rid="ref16">16</xref>), <italic>LRRK2</italic> (G2019S, R1441G) (<xref ref-type="bibr" rid="ref3">3</xref>, <xref ref-type="bibr" rid="ref30">30</xref>, <xref ref-type="bibr" rid="ref31">31</xref>), <italic>SNCA</italic> (E46K, A53T, duplication) (<xref ref-type="bibr" rid="ref8">8</xref>, <xref ref-type="bibr" rid="ref40">40</xref>, <xref ref-type="bibr" rid="ref41">41</xref>), and <italic>GBA</italic> (N370S, E326K, L444P, N409S/D409H) (<xref ref-type="bibr" rid="ref4">4</xref>, <xref ref-type="bibr" rid="ref5">5</xref>, <xref ref-type="bibr" rid="ref10">10</xref>, <xref ref-type="bibr" rid="ref52 ref53 ref54 ref55 ref56">52&#x2013;56</xref>) were identified in both skin biopsies and brain autopsies, with synucleinopathy detected in both cutaneous and cerebral samples. These results indicate that the same genotypes contribute to similar synucleinopathic changes in the central nervous system and peripheral skin. Conversely, skin biopsies and brain autopsies did not share mutation sites in <italic>DJ-1</italic> (<xref ref-type="bibr" rid="ref12">12</xref>, <xref ref-type="bibr" rid="ref62">62</xref>), <italic>PRKN</italic> (<xref ref-type="bibr" rid="ref6">6</xref>, <xref ref-type="bibr" rid="ref7">7</xref>, <xref ref-type="bibr" rid="ref11">11</xref>, <xref ref-type="bibr" rid="ref30">30</xref>, <xref ref-type="bibr" rid="ref63 ref64 ref65">63&#x2013;65</xref>, <xref ref-type="bibr" rid="ref67">67</xref>, <xref ref-type="bibr" rid="ref68">68</xref>), or <italic>RAB39B</italic> (<xref ref-type="bibr" rid="ref17">17</xref>, <xref ref-type="bibr" rid="ref18">18</xref>). Notably, we found Lewy body pathology in the brain autopsies of patients with the <italic>PRKN</italic> R275W point mutation. The R275W mutation, located in RING finger 1 of the parkin protein (amino acids 238&#x2013;293), alters protein distribution, leading to significant cytoplasmic and nuclear inclusions (<xref ref-type="bibr" rid="ref82">82</xref>). Patients with the <italic>PRKN</italic> R275 W mutation tend to have an earlier AAO and greater severity of disease than patients with two truncating mutations, suggesting a dominant negative effect (<xref ref-type="bibr" rid="ref82">82</xref>). Cookson et al. (<xref ref-type="bibr" rid="ref82">82</xref>) demonstrated that the intracellular inclusion bodies are aggresomes and a cellular response to misfolded proteins in primary cultured neurons. However, no &#x03B1;-syn deposits have been previously detected in PD patients with compound heterozygous R275 W/E3-4 deletion or R275 W/Pro113fs in skin biopsies and brain autopsies (<xref ref-type="bibr" rid="ref30">30</xref>, <xref ref-type="bibr" rid="ref66">66</xref>), hinting at the possibility that another mutation site may offset the negative effects of R275W&#x2014;a hypothesis that merits further research.</p>
<p>To some extent, certain gene mutations display ethnic specificity. In this study, the <italic>CHCHD2</italic> T61I mutation was exclusively detected in the skin biopsies and autopsies of Asian individuals, suggesting a potential Asian-specific prevalence of the T61I genotype. Similarly, the <italic>LRRK2</italic> G2385R mutation, which is strongly associated with PD in Asian populations (<xref ref-type="bibr" rid="ref83">83</xref>), was observed in both skin biopsies and brain autopsies of Asian individuals. Furthermore, skin biopsy synucleinopathy associated with the <italic>RAB39B</italic> E179fsX48 mutation was found solely in Asians, similar to that observed with <italic>CHCHD2</italic>, which needs further verification. Hence, our findings suggest that the <italic>CHCHD2</italic> T61I, <italic>LRRK2</italic> G2385R, and <italic>RAB39B</italic> E179fsX48 genotypes may predominantly occur in those with Asian ethnicity. These findings underscore the potential for the discovery of more ethnicity-specific genotypes related to cutaneous synucleinopathies, particularly within Asian cohorts, in future studies.</p>
<p>As a widely distributed neuronal protein, &#x03B1;-syn is highly enriched in presynaptic nerve terminals. The accumulation of misfolded oligomers and aggregates of &#x03B1;-syn, indicative of PD and other neurodegenerative synucleinopathies (<xref ref-type="bibr" rid="ref84">84</xref>), was observed within the somatosensory and autonomic nerves in skin biopsies of PD patients with <italic>CHCHD2</italic>, <italic>LRRK2</italic>, and <italic>GBA</italic> mutations in our study. Comparative immunohistochemical analyses highlighted 5G4 as an effective marker, revealing more extensive and distinct &#x03B1;-syn pathology compared to other aggregates. &#x03B1;-Synuclein oligomers are known to disrupt intracellular trafficking, elevate intracellular calcium levels, and lead to synaptic dysfunction and loss (<xref ref-type="bibr" rid="ref85">85</xref>). The detection of &#x03B1;-syn oligomers and aggregates in the peripheral nerves of skin biopsies aligns with the findings of our literature review of postmortem brain tissue in genetic PD patients.</p>
<p>In neurodegenerative diseases, especially in PD, intracellular &#x03B1;-syn and tau aggregates are commonly observed together, indicating co-neuropathology. The tau protein is subjected to extensive post-translational modifications, such as phosphorylation, deglycosylation, and truncation, resulting in insoluble, misfolded, and aggregated protein isoforms (<xref ref-type="bibr" rid="ref86">86</xref>). Notably, tau inclusions have been identified within nigral neurons of partially purified Lewy bodies, with some studies reporting tau inclusions in 50% of PD brains (<xref ref-type="bibr" rid="ref87">87</xref>). In this study, we detected tauopathies containing phosphorylated tau (AT8) and tau40 (HT7) deposited in skin nerves. Furthermore, tauopathies were observed in PD patients with <italic>RAB39B</italic> and <italic>PRKN</italic> mutations prior to the development of synucleinopathies, suggesting that tau accumulation may be upstream of &#x03B1;-syn aggregates. Thus, our findings on the peripheral cutaneous characteristics of genetic PD are consistent with previous reports that identified pathological tau as an early pre-synuclein process of nigrostriatal degeneration in premotor PD (<xref ref-type="bibr" rid="ref86">86</xref>).</p>
<p>In this study, the analysis of &#x03B1;-syn using SAA in skin biopsies showed unparalleled sensitivity and specificity for detecting iPD and PD in individuals with mutations in <italic>LRRK2</italic> G2385R and <italic>GBA</italic>. Originally developed for prion disease detection, the application of SAA to skin tissue facilitates seeding activity assessment. Recent applications on postmortem brain and CSF have successfully identified positive &#x03B1;-syn in patients with PD associated with the <italic>LRRK2</italic> G2019S mutation and Lewy body pathology, but not in those with the <italic>LRRK2</italic> R1441G mutation (<xref ref-type="bibr" rid="ref88">88</xref>). Therefore, prion-like seeding activity in peripheral skin may serve as an indicator of brain neuropathology in iPD and in certain cases of genetic PD. Consequently, &#x03B1;-syn SAA presents as a promising method for <italic>in vivo</italic> investigation of neuropathology in genetic PD.</p>
<p>Two research teams proposed biologically based staging systems for Parkinson&#x2019;s disease (PD) around the same time. One system, named the neuronal &#x03B1;-syn disease integrated staging system (NSD-ISS) (<xref ref-type="bibr" rid="ref89">89</xref>); The other approach, known as SynNeurGe, reflects the complexity and heterogeneity of PD using a three-component system (<xref ref-type="bibr" rid="ref90">90</xref>). Both concepts are supported by advances in biomarkers, allowing for the accurate detection of pathological &#x03B1;-syn in tissue or CSF using SAA. Our discovery of peripheral cutaneous synucleinopathy in genetic PD cases provides further evidence to support these staging systems.</p>
<p>One of the primary limitations of this study is its small sample size. However, given the rarity of genetic PD and its significance in exploring pathogenesis of PD, our research still provides valuable insights into peripheral cutaneous synucleinopathy in individuals with iPD and genetic PD. Another limitation of this study is the absence of synucleinopathic data from both skin biopsies and autopsy samples for the same genetic PD patient, complicated by cultural considerations that impact the feasibility of performing autopsies in Asian populations. Future studies, incorporating long-term observations of genetic PD cohorts, are needed to obtain in-depth clinical data and speculate on the possible pathogenesis of this disease.</p>
<p>In conclusion, our study of peripheral cutaneous synucleinopathy characteristics in patients with genetic PD yielded several key findings: (i) P-&#x03B1;-syn was deposited in the peripheral cutaneous nerves of PD patients with <italic>CHCHD2</italic>, <italic>LRRK2</italic>, or <italic>GBA</italic> mutations but not in those with <italic>RAB39B</italic> or <italic>PRKN</italic> mutations. (ii) The distribution and frequency of &#x03B1;-syn-positive deposits did not significantly differ between genetic PD and iPD patients. (iii) Peripheral cutaneous synucleinopathy closely mirrored the intracranial synucleinopathy observed in genetic PD, especially in AD-PD. (iv) The detection of peripheral cutaneous synucleinopathy through RT-QuIC may enhance diagnostic precision for PD diagnosis in future applications. Thus, peripheral skin biopsies may serve as an effective approach for identifying biomarkers of iPD and genetic PD. Further studies on cutaneous synucleinopathy in genetic PD patients should help in elucidating the pathophysiology of genetic PD and developing precise therapeutic interventions.</p>
</sec>
<sec sec-type="data-availability" id="sec23">
<title>Data availability statement</title>
<p>The original contributions presented in the study are included in the article/<xref ref-type="sec" rid="sec28">Supplementary material</xref>, further inquiries can be directed to the corresponding authors.</p>
</sec>
<sec sec-type="ethics-statement" id="sec24">
<title>Ethics statement</title>
<p>The studies involving humans were approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.</p>
</sec>
<sec sec-type="author-contributions" id="sec25">
<title>Author contributions</title>
<p>YY: Supervision, Software, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization, Writing &#x2013; review &#x0026; editing, Writing &#x2013; original draft. YW: Validation, Writing &#x2013; original draft. ML: Writing &#x2013; original draft, Methodology, Investigation. HL: Writing &#x2013; original draft, Methodology, Data curation. XL: Writing &#x2013; original draft, Methodology, Investigation. LL: Writing &#x2013; original draft, Formal analysis, Data curation. CM: Writing &#x2013; original draft, Investigation, Data curation. TY: Writing &#x2013; original draft, Methodology. SL: Writing &#x2013; original draft, Methodology. XZ: Writing &#x2013; original draft, Funding acquisition. YG: Writing &#x2013; original draft, Supervision. YX: Writing &#x2013; review &#x0026; editing, Visualization, Supervision, Software, Funding acquisition. JY: Writing &#x2013; review &#x0026; editing, Supervision, Software, Methodology, Funding acquisition.</p>
</sec>
</body>
<back>
<sec sec-type="funding-information" id="sec26">
<title>Funding</title>
<p>The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from the National Natural Science Foundation of China to YY (82201598), National Natural Science Foundation of China to YX (81530037), National Natural Science Foundation of China to JY (81600946), Provincial and Ministry of Health Construction Committee of Henan Province to JY (SB201902012), Funding for Scientific Research and Innovation Team of the First Affiliated Hospital of Zhengzhou University to JY (QNCXTD2023016), and Henan Province Medical Science and Technology Key Projects to YY (LHGJ20190077) and XZ (LHGJ20190083).</p>
</sec>
<sec sec-type="COI-statement" id="sec27">
<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>
<sec id="sec100" sec-type="disclaimer">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
<sec sec-type="supplementary-material" id="sec28">
<title>Supplementary material</title>
<p>The Supplementary material for this article can be found online at: <ext-link xlink:href="https://www.frontiersin.org/articles/10.3389/fneur.2024.1404492/full#supplementary-material" ext-link-type="uri">https://www.frontiersin.org/articles/10.3389/fneur.2024.1404492/full#supplementary-material</ext-link></p>
<supplementary-material xlink:href="Table_1.DOCX" id="SM1" mimetype="application/vnd.openxmlformats-officedocument.wordprocessingml.document" xmlns:xlink="http://www.w3.org/1999/xlink"/>
</sec>
<ref-list>
<title>References</title>
<ref id="ref1"><label>1.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kalia</surname> <given-names>LV</given-names></name> <name><surname>Lang</surname> <given-names>AE</given-names></name></person-group>. <article-title>Parkinson's disease</article-title>. <source>Lancet</source>. (<year>2015</year>) <volume>386</volume>:<fpage>896</fpage>&#x2013;<lpage>912</lpage>. doi: <pub-id pub-id-type="doi">10.1016/S0140-6736(14)61393-3</pub-id></citation></ref>
<ref id="ref2"><label>2.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Deng</surname> <given-names>H</given-names></name> <name><surname>Wang</surname> <given-names>P</given-names></name> <name><surname>Jankovic</surname> <given-names>J</given-names></name></person-group>. <article-title>The genetics of Parkinson disease</article-title>. <source>Ageing Res Rev</source>. (<year>2018</year>) <volume>42</volume>:<fpage>72</fpage>&#x2013;<lpage>85</lpage>. doi: <pub-id pub-id-type="doi">10.1016/j.arr.2017.12.007</pub-id></citation></ref>
<ref id="ref3"><label>3.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Gaig</surname> <given-names>C</given-names></name> <name><surname>Ezquerra</surname> <given-names>M</given-names></name> <name><surname>Marti</surname> <given-names>MJ</given-names></name> <name><surname>Valldeoriola</surname> <given-names>F</given-names></name> <name><surname>Munoz</surname> <given-names>E</given-names></name> <name><surname>Llado</surname> <given-names>A</given-names></name> <etal/></person-group>. <article-title>Screening for the LRRK2 G2019S and codon-1441 mutations in a pathological series of parkinsonian syndromes and frontotemporal lobar degeneration</article-title>. <source>J Neurol Sci</source>. (<year>2008</year>) <volume>270</volume>:<fpage>94</fpage>&#x2013;<lpage>8</lpage>. doi: <pub-id pub-id-type="doi">10.1016/j.jns.2008.02.010</pub-id></citation></ref>
<ref id="ref4"><label>4.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Goker-Alpan</surname> <given-names>O</given-names></name> <name><surname>Giasson</surname> <given-names>BI</given-names></name> <name><surname>Eblan</surname> <given-names>MJ</given-names></name> <name><surname>Nguyen</surname> <given-names>J</given-names></name> <name><surname>Hurtig</surname> <given-names>HI</given-names></name> <name><surname>Lee</surname> <given-names>VM</given-names></name> <etal/></person-group>. <article-title>Glucocerebrosidase mutations are an important risk factor for Lewy body disorders</article-title>. <source>Neurology</source>. (<year>2006</year>) <volume>67</volume>:<fpage>908</fpage>&#x2013;<lpage>10</lpage>. doi: <pub-id pub-id-type="doi">10.1212/01.wnl.0000230215.41296.18</pub-id></citation></ref>
<ref id="ref5"><label>5.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Goker-Alpan</surname> <given-names>O</given-names></name> <name><surname>Stubblefield</surname> <given-names>BK</given-names></name> <name><surname>Giasson</surname> <given-names>BI</given-names></name> <name><surname>Sidransky</surname> <given-names>E</given-names></name></person-group>. <article-title>Glucocerebrosidase is present in alpha-synuclein inclusions in Lewy body disorders</article-title>. <source>Acta Neuropathol</source>. (<year>2010</year>) <volume>120</volume>:<fpage>641</fpage>&#x2013;<lpage>9</lpage>. doi: <pub-id pub-id-type="doi">10.1007/s00401-010-0741-7</pub-id>, PMID: <pub-id pub-id-type="pmid">20838799</pub-id></citation></ref>
<ref id="ref6"><label>6.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Pramstaller</surname> <given-names>PP</given-names></name> <name><surname>Schlossmacher</surname> <given-names>MG</given-names></name> <name><surname>Jacques</surname> <given-names>TS</given-names></name> <name><surname>Scaravilli</surname> <given-names>F</given-names></name> <name><surname>Eskelson</surname> <given-names>C</given-names></name> <name><surname>Pepivani</surname> <given-names>I</given-names></name> <etal/></person-group>. <article-title>Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers</article-title>. <source>Ann Neurol</source>. (<year>2005</year>) <volume>58</volume>:<fpage>411</fpage>&#x2013;<lpage>22</lpage>. doi: <pub-id pub-id-type="doi">10.1002/ana.20587</pub-id></citation></ref>
<ref id="ref7"><label>7.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Miyakawa</surname> <given-names>S</given-names></name> <name><surname>Ogino</surname> <given-names>M</given-names></name> <name><surname>Funabe</surname> <given-names>S</given-names></name> <name><surname>Uchino</surname> <given-names>A</given-names></name> <name><surname>Shimo</surname> <given-names>Y</given-names></name> <name><surname>Hattori</surname> <given-names>N</given-names></name> <etal/></person-group>. <article-title>Lewy body pathology in a patient with a homozygous parkin deletion</article-title>. <source>Mov Disord</source>. (<year>2013</year>) <volume>28</volume>:<fpage>388</fpage>&#x2013;<lpage>91</lpage>. doi: <pub-id pub-id-type="doi">10.1002/mds.25346</pub-id>, PMID: <pub-id pub-id-type="pmid">23401296</pub-id></citation></ref>
<ref id="ref8"><label>8.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Carmona-Abellan</surname> <given-names>M</given-names></name> <name><surname>Gabilondo</surname> <given-names>I</given-names></name> <name><surname>Murueta-Goyena</surname> <given-names>A</given-names></name> <name><surname>Khurana</surname> <given-names>V</given-names></name> <name><surname>Tijero</surname> <given-names>B</given-names></name> <name><surname>Luquin</surname> <given-names>MR</given-names></name> <etal/></person-group>. <article-title>Small fiber neuropathy and phosphorylated alpha-synuclein in the skin of E46K-SNCA mutation carriers</article-title>. <source>Parkinsonism Relat Disord</source>. (<year>2019</year>) <volume>65</volume>:<fpage>139</fpage>&#x2013;<lpage>45</lpage>. doi: <pub-id pub-id-type="doi">10.1016/j.parkreldis.2019.05.038</pub-id>, PMID: <pub-id pub-id-type="pmid">31178336</pub-id></citation></ref>
<ref id="ref9"><label>9.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Donadio Vincenzo</surname> <given-names>AI</given-names></name> <name><surname>Leta</surname> <given-names>V</given-names></name> <name><surname>Giannoccaro</surname> <given-names>MP</given-names></name> <name><surname>Scaglione</surname> <given-names>C</given-names></name> <name><surname>Martinelli</surname> <given-names>P</given-names></name> <name><surname>Capellari</surname> <given-names>S</given-names></name> <etal/></person-group>. <article-title>Skin nerve a-synuclein deposits A biomarker for idiopathic Parkinson disease</article-title>. <source>Neurology</source>. (<year>2014</year>) <volume>82</volume>:<fpage>1362</fpage>&#x2013;<lpage>9</lpage>. doi: <pub-id pub-id-type="doi">10.1212/WNL.0000000000000316</pub-id></citation></ref>
<ref id="ref10"><label>10.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Doppler</surname> <given-names>K</given-names></name> <name><surname>Brockmann</surname> <given-names>K</given-names></name> <name><surname>Sedghi</surname> <given-names>A</given-names></name> <name><surname>Wurster</surname> <given-names>I</given-names></name> <name><surname>Volkmann</surname> <given-names>J</given-names></name> <name><surname>Oertel</surname> <given-names>WH</given-names></name> <etal/></person-group>. <article-title>Dermal Phospho-alpha-Synuclein deposition in patients with Parkinson's disease and mutation of the Glucocerebrosidase gene</article-title>. <source>Front Neurol</source>. (<year>2018</year>) <volume>9</volume>:<fpage>9</fpage>. doi: <pub-id pub-id-type="doi">10.3389/fneur.2018.01094</pub-id></citation></ref>
<ref id="ref11"><label>11.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Fadda</surname> <given-names>L</given-names></name> <name><surname>Lombardi</surname> <given-names>R</given-names></name> <name><surname>Soliveri</surname> <given-names>P</given-names></name> <name><surname>Lauria</surname> <given-names>G</given-names></name> <name><surname>Giovanni</surname> <given-names>D</given-names></name> <name><surname>Tagliavini</surname> <given-names>F</given-names></name></person-group>. <article-title>Skin nerve &#x03B1;-synuclein deposits in a parkinsonian patient with heterozygous parkin mutation</article-title>. <source>Parkinsonism Relat Disord</source>. (<year>2019</year>) <volume>60</volume>:<fpage>182</fpage>&#x2013;<lpage>3</lpage>. doi: <pub-id pub-id-type="doi">10.1016/j.parkreldis.2018.09.019</pub-id>, PMID: <pub-id pub-id-type="pmid">30245173</pub-id></citation></ref>
<ref id="ref12"><label>12.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Narendra</surname> <given-names>DP</given-names></name> <name><surname>Isonaka</surname> <given-names>R</given-names></name> <name><surname>Nguyen</surname> <given-names>D</given-names></name> <name><surname>Schindler</surname> <given-names>AB</given-names></name> <name><surname>Kokkinis</surname> <given-names>AD</given-names></name> <name><surname>Ehrlich</surname> <given-names>D</given-names></name> <etal/></person-group>. <article-title>Peripheral synucleinopathy in a DJ1 patient with Parkinson disease, cataracts, and hearing loss</article-title>. <source>Neurology</source>. (<year>2019</year>) <volume>92</volume>:<fpage>1113</fpage>&#x2013;<lpage>5</lpage>. doi: <pub-id pub-id-type="doi">10.1212/WNL.0000000000007614</pub-id>, PMID: <pub-id pub-id-type="pmid">31028127</pub-id></citation></ref>
<ref id="ref13"><label>13.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Yang</surname> <given-names>J</given-names></name> <name><surname>Wang</surname> <given-names>H</given-names></name> <name><surname>Yuan</surname> <given-names>Y</given-names></name> <name><surname>Fan</surname> <given-names>S</given-names></name> <name><surname>Li</surname> <given-names>L</given-names></name> <name><surname>Jiang</surname> <given-names>C</given-names></name> <etal/></person-group>. <article-title>Peripheral synucleinopathy in Parkinson disease with LRRK2 G2385R variants</article-title>. <source>Ann Clin Transl Neurol</source>. (<year>2021</year>) <volume>8</volume>:<fpage>592</fpage>&#x2013;<lpage>602</lpage>. doi: <pub-id pub-id-type="doi">10.1002/acn3.51301</pub-id>, PMID: <pub-id pub-id-type="pmid">33527742</pub-id></citation></ref>
<ref id="ref14"><label>14.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Shi</surname> <given-names>CH</given-names></name> <name><surname>Mao</surname> <given-names>CY</given-names></name> <name><surname>Zhang</surname> <given-names>SY</given-names></name> <name><surname>Yang</surname> <given-names>J</given-names></name> <name><surname>Song</surname> <given-names>B</given-names></name> <name><surname>Wu</surname> <given-names>P</given-names></name> <etal/></person-group>. <article-title>CHCHD2 gene mutations in familial and sporadic Parkinson's disease</article-title>. <source>Neurobiol Aging</source>. (<year>2016</year>) <volume>38</volume>:<fpage>217.e9</fpage>&#x2013;<lpage>217.e13</lpage>. doi: <pub-id pub-id-type="doi">10.1016/j.neurobiolaging.2015.10.040</pub-id></citation></ref>
<ref id="ref15"><label>15.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Shi</surname> <given-names>CH</given-names></name> <name><surname>Zhang</surname> <given-names>SY</given-names></name> <name><surname>Yang</surname> <given-names>ZH</given-names></name> <name><surname>Yang</surname> <given-names>J</given-names></name> <name><surname>Shang</surname> <given-names>DD</given-names></name> <name><surname>Mao</surname> <given-names>CY</given-names></name> <etal/></person-group>. <article-title>A novel RAB39B gene mutation in X-linked juvenile parkinsonism with basal ganglia calcification</article-title>. <source>Mov Disord</source>. (<year>2016</year>) <volume>31</volume>:<fpage>1905</fpage>&#x2013;<lpage>9</lpage>. doi: <pub-id pub-id-type="doi">10.1002/mds.26828</pub-id>, PMID: <pub-id pub-id-type="pmid">27943471</pub-id></citation></ref>
<ref id="ref16"><label>16.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ikeda</surname> <given-names>A</given-names></name> <name><surname>Nishioka</surname> <given-names>K</given-names></name> <name><surname>Meng</surname> <given-names>H</given-names></name> <name><surname>Takanashi</surname> <given-names>M</given-names></name> <name><surname>Hasegawa</surname> <given-names>I</given-names></name> <name><surname>Inoshita</surname> <given-names>T</given-names></name> <etal/></person-group>. <article-title>Mutations in CHCHD2 cause alpha-synuclein aggregation</article-title>. <source>Hum Mol Genet</source>. (<year>2019</year>) <volume>28</volume>:<fpage>3895</fpage>&#x2013;<lpage>911</lpage>. doi: <pub-id pub-id-type="doi">10.1093/hmg/ddz241</pub-id>, PMID: <pub-id pub-id-type="pmid">31600778</pub-id></citation></ref>
<ref id="ref17"><label>17.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wilson</surname> <given-names>GR</given-names></name> <name><surname>Sim</surname> <given-names>JC</given-names></name> <name><surname>McLean</surname> <given-names>C</given-names></name> <name><surname>Giannandrea</surname> <given-names>M</given-names></name> <name><surname>Galea</surname> <given-names>CA</given-names></name> <name><surname>Riseley</surname> <given-names>JR</given-names></name> <etal/></person-group>. <article-title>Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with alpha-synuclein pathology</article-title>. <source>Am J Hum Genet</source>. (<year>2014</year>) <volume>95</volume>:<fpage>729</fpage>&#x2013;<lpage>35</lpage>. doi: <pub-id pub-id-type="doi">10.1016/j.ajhg.2014.10.015</pub-id>, PMID: <pub-id pub-id-type="pmid">25434005</pub-id></citation></ref>
<ref id="ref18"><label>18.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Gao</surname> <given-names>Y</given-names></name> <name><surname>Martinez-Cerdeno</surname> <given-names>V</given-names></name> <name><surname>Hogan</surname> <given-names>KJ</given-names></name> <name><surname>McLean</surname> <given-names>CA</given-names></name> <name><surname>Lockhart</surname> <given-names>PJ</given-names></name></person-group>. <article-title>Clinical and neuropathological features associated with loss of RAB39B</article-title>. <source>Mov Disord</source>. (<year>2020</year>) <volume>35</volume>:<fpage>687</fpage>&#x2013;<lpage>93</lpage>. doi: <pub-id pub-id-type="doi">10.1002/mds.27951</pub-id>, PMID: <pub-id pub-id-type="pmid">31951675</pub-id></citation></ref>
<ref id="ref19"><label>19.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Orr&#x00FA;</surname> <given-names>C</given-names></name> <name><surname>Yuan</surname> <given-names>J</given-names></name> <name><surname>Appleby</surname> <given-names>B</given-names></name> <name><surname>Li</surname> <given-names>B</given-names></name> <name><surname>Li</surname> <given-names>Y</given-names></name> <name><surname>Winner</surname> <given-names>D</given-names></name> <etal/></person-group>. <article-title>Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease</article-title>. <source>Sci Transl Med</source>. (<year>2017</year>) <volume>9</volume>:<fpage>7785</fpage>. doi: <pub-id pub-id-type="doi">10.1126/scitranslmed.aam7785</pub-id>, PMID: <pub-id pub-id-type="pmid">29167394</pub-id></citation></ref>
<ref id="ref20"><label>20.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Donadio</surname> <given-names>V</given-names></name> <name><surname>Wang</surname> <given-names>Z</given-names></name> <name><surname>Incensi</surname> <given-names>A</given-names></name> <name><surname>Rizzo</surname> <given-names>G</given-names></name> <name><surname>Fileccia</surname> <given-names>E</given-names></name> <name><surname>Vacchiano</surname> <given-names>V</given-names></name> <etal/></person-group>. <article-title>In vivo diagnosis of Synucleinopathies</article-title>. <source>Neurology</source>. (<year>2021</year>) <volume>96</volume>:<fpage>20</fpage>. doi: <pub-id pub-id-type="doi">10.1212/WNL.0000000000011935</pub-id></citation></ref>
<ref id="ref21"><label>21.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Srivastava</surname> <given-names>A</given-names></name> <name><surname>Alam</surname> <given-names>P</given-names></name> <name><surname>Caughey</surname> <given-names>B</given-names></name></person-group>. <article-title>RT-QuIC and related assays for detecting and quantifying prion-like pathological seeds of &#x03B1;-Synuclein</article-title>. <source>Biomol Ther</source>. (<year>2022</year>) <volume>12</volume>:<fpage>576</fpage>. doi: <pub-id pub-id-type="doi">10.3390/biom12040576</pub-id>, PMID: <pub-id pub-id-type="pmid">35454165</pub-id></citation></ref>
<ref id="ref22"><label>22.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname> <given-names>Z</given-names></name> <name><surname>Becker</surname> <given-names>K</given-names></name> <name><surname>Donadio</surname> <given-names>V</given-names></name> <name><surname>Siedlak</surname> <given-names>S</given-names></name> <name><surname>Yuan</surname> <given-names>J</given-names></name> <name><surname>Rezaee</surname> <given-names>M</given-names></name> <etal/></person-group>. <article-title>Skin &#x03B1;-Synuclein aggregation seeding activity as a novel biomarker for Parkinson disease</article-title>. <source>JAMA Neurol</source>. (<year>2021</year>) <volume>78</volume>:<fpage>30</fpage>&#x2013;<lpage>11</lpage>. doi: <pub-id pub-id-type="doi">10.1001/jamaneurol.2020.3311</pub-id>, PMID: <pub-id pub-id-type="pmid">32986090</pub-id></citation></ref>
<ref id="ref23"><label>23.</label><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>. <article-title>Discriminating &#x03B1;-synuclein strains in Parkinson&#x2019;s disease and multiple system atrophy</article-title>. <source>Nature</source>. (<year>2020</year>) <volume>578</volume>:<fpage>273</fpage>&#x2013;<lpage>7</lpage>. doi: <pub-id pub-id-type="doi">10.1038/s41586-020-1984-7</pub-id>, PMID: <pub-id pub-id-type="pmid">32025029</pub-id></citation></ref>
<ref id="ref24"><label>24.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Donadio</surname> <given-names>V</given-names></name></person-group>. <article-title>Skin nerve &#x03B1;-synuclein deposits in Parkinson&#x2019;s disease and other synucleinopathies: a review</article-title>. <source>Clin Auton Res</source>. (<year>2018</year>) <volume>29</volume>:<fpage>577</fpage>&#x2013;<lpage>85</lpage>. doi: <pub-id pub-id-type="doi">10.1007/s10286-018-0581-4</pub-id>, PMID: <pub-id pub-id-type="pmid">30506233</pub-id></citation></ref>
<ref id="ref25"><label>25.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Doppler</surname> <given-names>K</given-names></name> <name><surname>Volkmann</surname> <given-names>J</given-names></name> <name><surname>Sommer</surname> <given-names>C</given-names></name></person-group>. <article-title>Skin biopsies in the differential diagnosis of parkinsonism: are we ready for simplified protocols?</article-title> <source>Brain</source>. (<year>2016</year>) <volume>139</volume>:<fpage>e5</fpage>. doi: <pub-id pub-id-type="doi">10.1093/brain/awv251</pub-id></citation></ref>
<ref id="ref26"><label>26.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Postuma</surname> <given-names>RB</given-names></name> <name><surname>Berg</surname> <given-names>D</given-names></name> <name><surname>Stern</surname> <given-names>M</given-names></name> <name><surname>Poewe</surname> <given-names>W</given-names></name> <name><surname>Olanow</surname> <given-names>CW</given-names></name> <name><surname>Oertel</surname> <given-names>W</given-names></name> <etal/></person-group>. <article-title>MDS clinical diagnostic criteria for Parkinson's disease</article-title>. <source>Mov Disord</source>. (<year>2015</year>) <volume>30</volume>:<fpage>1591</fpage>&#x2013;<lpage>601</lpage>. doi: <pub-id pub-id-type="doi">10.1002/mds.26424</pub-id></citation></ref>
<ref id="ref27"><label>27.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Goetz</surname> <given-names>CG</given-names></name> <name><surname>Stebbins</surname> <given-names>GT</given-names></name> <name><surname>Tilley</surname> <given-names>BC</given-names></name></person-group>. <article-title>Calibration of unified Parkinson's disease rating scale scores to Movement Disorder Society-unified Parkinson's disease rating scale scores</article-title>. <source>Mov Disord</source>. (<year>2012</year>) <volume>27</volume>:<fpage>1239</fpage>&#x2013;<lpage>42</lpage>. doi: <pub-id pub-id-type="doi">10.1002/mds.25122</pub-id>, PMID: <pub-id pub-id-type="pmid">22886777</pub-id></citation></ref>
<ref id="ref28"><label>28.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Gupta</surname> <given-names>DK</given-names></name> <name><surname>Fahn</surname> <given-names>S</given-names></name> <name><surname>Tatsuoka</surname> <given-names>C</given-names></name> <name><surname>Kang</surname> <given-names>UJ</given-names></name></person-group>. <article-title>Hoehn and Yahr stage 3 and postural stability item in the movement disorder society-unified Parkinson's disease rating scale</article-title>. <source>Mov Disord</source>. (<year>2018</year>) <volume>33</volume>:<fpage>1188</fpage>&#x2013;<lpage>9</lpage>. doi: <pub-id pub-id-type="doi">10.1002/mds.27453</pub-id></citation></ref>
<ref id="ref29"><label>29.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Chaudhuri</surname> <given-names>KR</given-names></name> <name><surname>Martinez-Martin</surname> <given-names>P</given-names></name> <name><surname>Brown</surname> <given-names>RG</given-names></name> <name><surname>Sethi</surname> <given-names>K</given-names></name> <name><surname>Stocchi</surname> <given-names>F</given-names></name> <name><surname>Odin</surname> <given-names>P</given-names></name> <etal/></person-group>. <article-title>The metric properties of a novel non-motor symptoms scale for Parkinson's disease: results from an international pilot study</article-title>. <source>Mov Disord</source>. (<year>2007</year>) <volume>22</volume>:<fpage>1901</fpage>&#x2013;<lpage>11</lpage>. doi: <pub-id pub-id-type="doi">10.1002/mds.21596</pub-id>, PMID: <pub-id pub-id-type="pmid">17674410</pub-id></citation></ref>
<ref id="ref30"><label>30.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Isonaka</surname> <given-names>R</given-names></name> <name><surname>Goldstein</surname> <given-names>DS</given-names></name> <name><surname>Zhu</surname> <given-names>W</given-names></name> <name><surname>Yoon</surname> <given-names>E</given-names></name> <name><surname>Ehrlich</surname> <given-names>D</given-names></name> <name><surname>Schindler</surname> <given-names>AB</given-names></name> <etal/></person-group>. <article-title>Alpha-Synuclein deposition in sympathetic nerve fibers in genetic forms of Parkinson's disease</article-title>. <source>Mov Disord</source>. (<year>2021</year>) <volume>36</volume>:<fpage>2346</fpage>&#x2013;<lpage>57</lpage>. doi: <pub-id pub-id-type="doi">10.1002/mds.28667</pub-id>, PMID: <pub-id pub-id-type="pmid">34076298</pub-id></citation></ref>
<ref id="ref31"><label>31.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Mamais</surname> <given-names>A</given-names></name> <name><surname>Raja</surname> <given-names>M</given-names></name> <name><surname>Manzoni</surname> <given-names>C</given-names></name> <name><surname>Dihanich</surname> <given-names>S</given-names></name> <name><surname>Lees</surname> <given-names>A</given-names></name> <name><surname>Moore</surname> <given-names>D</given-names></name> <etal/></person-group>. <article-title>Divergent alpha-synuclein solubility and aggregation properties in G2019S LRRK2 Parkinson's disease brains with Lewy body pathology compared to idiopathic cases</article-title>. <source>Neurobiol Dis</source>. (<year>2013</year>) <volume>58</volume>:<fpage>183</fpage>&#x2013;<lpage>90</lpage>. doi: <pub-id pub-id-type="doi">10.1016/j.nbd.2013.05.017</pub-id>, PMID: <pub-id pub-id-type="pmid">23747310</pub-id></citation></ref>
<ref id="ref32"><label>32.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Gilks</surname> <given-names>WP</given-names></name> <name><surname>Abou-Sleiman</surname> <given-names>PM</given-names></name> <name><surname>Gandhi</surname> <given-names>S</given-names></name> <name><surname>Jain</surname> <given-names>S</given-names></name> <name><surname>Singleton</surname> <given-names>A</given-names></name> <name><surname>Lees</surname> <given-names>AJ</given-names></name> <etal/></person-group>. <article-title>A common LRRK2 mutation in idiopathic Parkinson's disease</article-title>. <source>Lancet</source>. (<year>2005</year>) <volume>365</volume>:<fpage>415</fpage>&#x2013;<lpage>6</lpage>. doi: <pub-id pub-id-type="doi">10.1016/S0140-6736(05)17830-1</pub-id>, PMID: <pub-id pub-id-type="pmid">15680457</pub-id></citation></ref>
<ref id="ref33"><label>33.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ross</surname> <given-names>OA</given-names></name> <name><surname>Toft</surname> <given-names>M</given-names></name> <name><surname>Whittle</surname> <given-names>AJ</given-names></name> <name><surname>Johnson</surname> <given-names>JL</given-names></name> <name><surname>Papapetropoulos</surname> <given-names>S</given-names></name> <name><surname>Mash</surname> <given-names>DC</given-names></name> <etal/></person-group>. <article-title>Lrrk2 and Lewy body disease</article-title>. <source>Ann Neurol</source>. (<year>2006</year>) <volume>59</volume>:<fpage>388</fpage>&#x2013;<lpage>93</lpage>. doi: <pub-id pub-id-type="doi">10.1002/ana.20731</pub-id></citation></ref>
<ref id="ref34"><label>34.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Poulopoulos</surname> <given-names>M</given-names></name> <name><surname>Levy</surname> <given-names>OA</given-names></name> <name><surname>Alcalay</surname> <given-names>RN</given-names></name></person-group>. <article-title>The neuropathology of genetic Parkinson's disease</article-title>. <source>Mov Disord</source>. (<year>2012</year>) <volume>27</volume>:<fpage>831</fpage>&#x2013;<lpage>42</lpage>. doi: <pub-id pub-id-type="doi">10.1002/mds.24962</pub-id></citation></ref>
<ref id="ref35"><label>35.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kalia</surname> <given-names>LV</given-names></name> <name><surname>Lang</surname> <given-names>AE</given-names></name> <name><surname>Hazrati</surname> <given-names>LN</given-names></name> <name><surname>Fujioka</surname> <given-names>S</given-names></name> <name><surname>Wszolek</surname> <given-names>ZK</given-names></name> <name><surname>Dickson</surname> <given-names>DW</given-names></name> <etal/></person-group>. <article-title>Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease</article-title>. <source>JAMA Neurol</source>. (<year>2015</year>) <volume>72</volume>:<fpage>100</fpage>&#x2013;<lpage>5</lpage>. doi: <pub-id pub-id-type="doi">10.1001/jamaneurol.2014.2704</pub-id>, PMID: <pub-id pub-id-type="pmid">25401511</pub-id></citation></ref>
<ref id="ref36"><label>36.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Marti-Masso</surname> <given-names>JF</given-names></name> <name><surname>Ruiz-Martinez</surname> <given-names>J</given-names></name> <name><surname>Bolano</surname> <given-names>MJ</given-names></name> <name><surname>Ruiz</surname> <given-names>I</given-names></name> <name><surname>Gorostidi</surname> <given-names>A</given-names></name> <name><surname>Moreno</surname> <given-names>F</given-names></name> <etal/></person-group>. <article-title>Neuropathology of Parkinson's disease with the R1441G mutation in LRRK2</article-title>. <source>Mov Disord</source>. (<year>2009</year>) <volume>24</volume>:<fpage>1998</fpage>&#x2013;<lpage>2001</lpage>. doi: <pub-id pub-id-type="doi">10.1002/mds.22677</pub-id>, PMID: <pub-id pub-id-type="pmid">19735093</pub-id></citation></ref>
<ref id="ref37"><label>37.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Zimprich</surname> <given-names>A</given-names></name> <name><surname>Biskup</surname> <given-names>S</given-names></name> <name><surname>Leitner</surname> <given-names>P</given-names></name> <name><surname>Lichtner</surname> <given-names>P</given-names></name> <name><surname>Farrer</surname> <given-names>M</given-names></name> <name><surname>Lincoln</surname> <given-names>S</given-names></name> <etal/></person-group>. <article-title>Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology</article-title>. <source>Neuron</source>. (<year>2004</year>) <volume>44</volume>:<fpage>601</fpage>&#x2013;<lpage>7</lpage>. doi: <pub-id pub-id-type="doi">10.1016/j.neuron.2004.11.005</pub-id>, PMID: <pub-id pub-id-type="pmid">15541309</pub-id></citation></ref>
<ref id="ref38"><label>38.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Puschmann</surname> <given-names>A</given-names></name> <name><surname>Englund</surname> <given-names>E</given-names></name> <name><surname>Ross</surname> <given-names>OA</given-names></name> <name><surname>Vilarino-Guell</surname> <given-names>C</given-names></name> <name><surname>Lincoln</surname> <given-names>SJ</given-names></name> <name><surname>Kachergus</surname> <given-names>JM</given-names></name> <etal/></person-group>. <article-title>First neuropathological description of a patient with Parkinson's disease and LRRK2 p.N1437H mutation</article-title>. <source>Parkinsonism Relat Disord</source>. (<year>2012</year>) <volume>18</volume>:<fpage>332</fpage>&#x2013;<lpage>8</lpage>. doi: <pub-id pub-id-type="doi">10.1016/j.parkreldis.2011.11.019</pub-id></citation></ref>
<ref id="ref39"><label>39.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Khan</surname> <given-names>NL</given-names></name> <name><surname>Jain</surname> <given-names>S</given-names></name> <name><surname>Lynch</surname> <given-names>JM</given-names></name> <name><surname>Pavese</surname> <given-names>N</given-names></name> <name><surname>Abou-Sleiman</surname> <given-names>P</given-names></name> <name><surname>Holton</surname> <given-names>JL</given-names></name> <etal/></person-group>. <article-title>Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data</article-title>. <source>Brain</source>. (<year>2005</year>) <volume>128</volume>:<fpage>2786</fpage>&#x2013;<lpage>96</lpage>. doi: <pub-id pub-id-type="doi">10.1093/brain/awh667</pub-id>, PMID: <pub-id pub-id-type="pmid">16272164</pub-id></citation></ref>
<ref id="ref40"><label>40.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Zarranz</surname> <given-names>JJ</given-names></name> <name><surname>Alegre</surname> <given-names>J</given-names></name> <name><surname>Juan</surname> <given-names>C</given-names></name> <name><surname>Gomez-Esteban</surname> <given-names>EL</given-names></name> <name><surname>Ros</surname> <given-names>R</given-names></name> <name><surname>Ampuero</surname> <given-names>I</given-names></name> <etal/></person-group>. <article-title>The new mutation E46K of a synuclein causes Parkinson and Lewy body dementia</article-title>. <source>Ann Neurol</source>. (<year>2004</year>) <volume>55</volume>:<fpage>164</fpage>&#x2013;<lpage>73</lpage>. doi: <pub-id pub-id-type="doi">10.1002/ana.10795</pub-id>, PMID: <pub-id pub-id-type="pmid">14755719</pub-id></citation></ref>
<ref id="ref41"><label>41.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Duda</surname> <given-names>JE</given-names></name> <name><surname>Giasson</surname> <given-names>BI</given-names></name> <name><surname>Mabon</surname> <given-names>ME</given-names></name> <name><surname>Miller</surname> <given-names>DC</given-names></name> <name><surname>Golbe</surname> <given-names>LI</given-names></name> <name><surname>Lee</surname> <given-names>VM</given-names></name> <etal/></person-group>. <article-title>Concurrence of alpha-synuclein and tau brain pathology in the Contursi kindred</article-title>. <source>Acta Neuropathol</source>. (<year>2002</year>) <volume>104</volume>:<fpage>7</fpage>&#x2013;<lpage>11</lpage>. doi: <pub-id pub-id-type="doi">10.1007/s00401-002-0563-3</pub-id>, PMID: <pub-id pub-id-type="pmid">12070658</pub-id></citation></ref>
<ref id="ref42"><label>42.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Markopoulou</surname> <given-names>K</given-names></name> <name><surname>Dickson</surname> <given-names>DW</given-names></name> <name><surname>McComb</surname> <given-names>RD</given-names></name> <name><surname>Wszolek</surname> <given-names>ZK</given-names></name> <name><surname>Katechalidou</surname> <given-names>L</given-names></name> <name><surname>Avery</surname> <given-names>L</given-names></name> <etal/></person-group>. <article-title>Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson's disease. Variability in familial Parkinson's disease</article-title>. <source>Acta Neuropathol</source>. (<year>2008</year>) <volume>116</volume>:<fpage>25</fpage>&#x2013;<lpage>35</lpage>. doi: <pub-id pub-id-type="doi">10.1007/s00401-008-0372-4</pub-id>, PMID: <pub-id pub-id-type="pmid">18389263</pub-id></citation></ref>
<ref id="ref43"><label>43.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Pasanen</surname> <given-names>P</given-names></name> <name><surname>Myllykangas</surname> <given-names>L</given-names></name> <name><surname>Siitonen</surname> <given-names>M</given-names></name> <name><surname>Raunio</surname> <given-names>A</given-names></name> <name><surname>Kaakkola</surname> <given-names>S</given-names></name> <name><surname>Lyytinen</surname> <given-names>J</given-names></name> <etal/></person-group>. <article-title>Novel alpha-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson's disease-type pathology</article-title>. <source>Neurobiol Aging</source>. (<year>2014</year>) <volume>35</volume>:<fpage>2180.e1</fpage>&#x2013;<lpage>5</lpage>. doi: <pub-id pub-id-type="doi">10.1016/j.neurobiolaging.2014.03.024</pub-id></citation></ref>
<ref id="ref44"><label>44.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lawrence</surname> <given-names>I</given-names></name> <name><surname>Golbe</surname> <given-names>GDI</given-names></name> <name><surname>Bonavita</surname> <given-names>V</given-names></name> <name><surname>Miller</surname> <given-names>DC</given-names></name> <name><surname>Duvoisin</surname> <given-names>RC</given-names></name></person-group>. <article-title>A large kindred with autosomal dominant Parkinson's disease</article-title>. <source>Ann Neurol</source>. (<year>1990</year>) <volume>27</volume>:<fpage>276</fpage>&#x2013;<lpage>82</lpage>. doi: <pub-id pub-id-type="doi">10.1002/ana.410270309</pub-id></citation></ref>
<ref id="ref45"><label>45.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wakabayashi</surname> <given-names>K</given-names></name> <name><surname>Hayashi</surname> <given-names>S</given-names></name> <name><surname>Ishikawa</surname> <given-names>A</given-names></name> <name><surname>Hayashi</surname> <given-names>T</given-names></name> <name><surname>Okuizumi</surname> <given-names>K</given-names></name> <name><surname>Tanaka</surname> <given-names>H</given-names></name> <etal/></person-group>. <article-title>Autosomal dominant diffuse Lewy body disease</article-title>. <source>Acta Neuropathol</source>. (<year>1998</year>) <volume>96</volume>:<fpage>207</fpage>&#x2013;<lpage>10</lpage>. doi: <pub-id pub-id-type="doi">10.1007/s004010050883</pub-id></citation></ref>
<ref id="ref46"><label>46.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Obi</surname> <given-names>T</given-names></name> <name><surname>Nishioka</surname> <given-names>K</given-names></name> <name><surname>Ross</surname> <given-names>OA</given-names></name> <name><surname>Terada</surname> <given-names>T</given-names></name> <name><surname>Yamazaki</surname> <given-names>K</given-names></name> <name><surname>Sugiura</surname> <given-names>A</given-names></name> <etal/></person-group>. <article-title>Clinicopathologic study of a SNCA gene duplication patient with parkinson disease and dementia</article-title>. <source>Neurology</source>. (<year>2008</year>) <volume>70</volume>:<fpage>238</fpage>&#x2013;<lpage>41</lpage>. doi: <pub-id pub-id-type="doi">10.1212/01.wnl.0000299387.59159.db</pub-id>, PMID: <pub-id pub-id-type="pmid">18195271</pub-id></citation></ref>
<ref id="ref47"><label>47.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kara</surname> <given-names>E</given-names></name> <name><surname>Kiely</surname> <given-names>AP</given-names></name> <name><surname>Proukakis</surname> <given-names>C</given-names></name> <name><surname>Giffin</surname> <given-names>N</given-names></name> <name><surname>Love</surname> <given-names>S</given-names></name> <name><surname>Hehir</surname> <given-names>J</given-names></name> <etal/></person-group>. <article-title>A 6.4 Mb duplication of the alpha-synuclein locus causing frontotemporal dementia and parkinsonism: phenotype-genotype correlations</article-title>. <source>JAMA Neurol</source>. (<year>2014</year>) <volume>71</volume>:<fpage>1162</fpage>&#x2013;<lpage>71</lpage>. doi: <pub-id pub-id-type="doi">10.1001/jamaneurol.2014.994</pub-id>, PMID: <pub-id pub-id-type="pmid">25003242</pub-id></citation></ref>
<ref id="ref48"><label>48.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Konno</surname> <given-names>T</given-names></name> <name><surname>Ross</surname> <given-names>OA</given-names></name> <name><surname>Puschmann</surname> <given-names>A</given-names></name> <name><surname>Dickson</surname> <given-names>DW</given-names></name> <name><surname>Wszolek</surname> <given-names>ZK</given-names></name></person-group>. <article-title>Autosomal dominant Parkinson's disease caused by SNCA duplications</article-title>. <source>Parkinsonism Relat Disord</source>. (<year>2016</year>) <volume>22</volume>:<fpage>S1</fpage>&#x2013;<lpage>6</lpage>. doi: <pub-id pub-id-type="doi">10.1016/j.parkreldis.2015.09.007</pub-id>, PMID: <pub-id pub-id-type="pmid">26350119</pub-id></citation></ref>
<ref id="ref49"><label>49.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kiely</surname> <given-names>AP</given-names></name> <name><surname>Ling</surname> <given-names>H</given-names></name> <name><surname>Asi</surname> <given-names>YT</given-names></name> <name><surname>Kara</surname> <given-names>E</given-names></name> <name><surname>Proukakis</surname> <given-names>C</given-names></name> <name><surname>Schapira</surname> <given-names>AH</given-names></name> <etal/></person-group>. <article-title>Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation</article-title>. <source>Mol Neurodegener</source>. (<year>2015</year>) <volume>10</volume>:<fpage>41</fpage>. doi: <pub-id pub-id-type="doi">10.1186/s13024-015-0038-3</pub-id>, PMID: <pub-id pub-id-type="pmid">26306801</pub-id></citation></ref>
<ref id="ref50"><label>50.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Seidel</surname> <given-names>K</given-names></name> <name><surname>Schols</surname> <given-names>L</given-names></name> <name><surname>Nuber</surname> <given-names>S</given-names></name> <name><surname>Petrasch-Parwez</surname> <given-names>E</given-names></name> <name><surname>Gierga</surname> <given-names>K</given-names></name> <name><surname>Wszolek</surname> <given-names>Z</given-names></name> <etal/></person-group>. <article-title>First appraisal of brain pathology owing to A30P mutant alpha-synuclein</article-title>. <source>Ann Neurol</source>. (<year>2010</year>) <volume>67</volume>:<fpage>684</fpage>&#x2013;<lpage>9</lpage>. doi: <pub-id pub-id-type="doi">10.1002/ana.21966</pub-id>, PMID: <pub-id pub-id-type="pmid">20437567</pub-id></citation></ref>
<ref id="ref51"><label>51.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Manfred</surname> <given-names>D</given-names></name> <name><surname>Muenter</surname> <given-names>LSF</given-names></name> <name><surname>Oleh Hornykiewicz</surname> <given-names>S</given-names></name> <name><surname>Kish</surname> <given-names>SJ</given-names></name> <name><surname>Demetrius</surname> <given-names>S</given-names></name> <name><surname>Maraganore</surname> <given-names>M</given-names></name> <etal/></person-group>. <article-title>Hereditary form of parkinsonism dementia</article-title>. <source>Ann Neurol</source>. (<year>1998</year>) <volume>43</volume>:<fpage>768</fpage>&#x2013;<lpage>81</lpage>. doi: <pub-id pub-id-type="doi">10.1002/ana.410430612</pub-id></citation></ref>
<ref id="ref52"><label>52.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Clark</surname> <given-names>LN</given-names></name> <name><surname>Kartsaklis</surname> <given-names>LA</given-names></name> <name><surname>Wolf Gilbert</surname> <given-names>R</given-names></name> <name><surname>Dorado</surname> <given-names>B</given-names></name> <name><surname>Ross</surname> <given-names>BM</given-names></name> <name><surname>Kisselev</surname> <given-names>S</given-names></name> <etal/></person-group>. <article-title>Association of glucocerebrosidase mutations with dementia with lewy bodies</article-title>. <source>Arch Neurol</source>. (<year>2009</year>) <volume>66</volume>:<fpage>578</fpage>&#x2013;<lpage>83</lpage>. doi: <pub-id pub-id-type="doi">10.1001/archneurol.2009.54</pub-id>, PMID: <pub-id pub-id-type="pmid">19433657</pub-id></citation></ref>
<ref id="ref53"><label>53.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Sklerov</surname> <given-names>M</given-names></name> <name><surname>Kang</surname> <given-names>UJ</given-names></name> <name><surname>Liong</surname> <given-names>C</given-names></name> <name><surname>Clark</surname> <given-names>L</given-names></name> <name><surname>Marder</surname> <given-names>K</given-names></name> <name><surname>Pauciulo</surname> <given-names>M</given-names></name> <etal/></person-group>. <article-title>Frequency of GBA variants in autopsy-proven multiple system atrophy</article-title>. <source>Mov Disord Clin Pract</source>. (<year>2017</year>) <volume>4</volume>:<fpage>574</fpage>&#x2013;<lpage>81</lpage>. doi: <pub-id pub-id-type="doi">10.1002/mdc3.12481</pub-id>, PMID: <pub-id pub-id-type="pmid">28966932</pub-id></citation></ref>
<ref id="ref54"><label>54.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Tayebi</surname> <given-names>N</given-names></name></person-group>. <article-title>Gaucher disease with parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism?</article-title> <source>Mol Genet Metab</source>. (<year>2003</year>) <volume>79</volume>:<fpage>104</fpage>&#x2013;<lpage>9</lpage>. doi: <pub-id pub-id-type="doi">10.1016/S1096-7192(03)00071-4</pub-id>, PMID: <pub-id pub-id-type="pmid">12809640</pub-id></citation></ref>
<ref id="ref55"><label>55.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Nishioka</surname> <given-names>K</given-names></name> <name><surname>Ross</surname> <given-names>OA</given-names></name> <name><surname>Vilarino-Guell</surname> <given-names>C</given-names></name> <name><surname>Cobb</surname> <given-names>SA</given-names></name> <name><surname>Kachergus</surname> <given-names>JM</given-names></name> <name><surname>Mann</surname> <given-names>DM</given-names></name> <etal/></person-group>. <article-title>Glucocerebrosidase mutations in diffuse Lewy body disease</article-title>. <source>Parkinsonism Relat Disord</source>. (<year>2011</year>) <volume>17</volume>:<fpage>55</fpage>&#x2013;<lpage>7</lpage>. doi: <pub-id pub-id-type="doi">10.1016/j.parkreldis.2010.09.009</pub-id>, PMID: <pub-id pub-id-type="pmid">20971030</pub-id></citation></ref>
<ref id="ref56"><label>56.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wong</surname> <given-names>K</given-names></name> <name><surname>Sidransky</surname> <given-names>E</given-names></name> <name><surname>Verma</surname> <given-names>A</given-names></name> <name><surname>Mixon</surname> <given-names>T</given-names></name> <name><surname>Sandberg</surname> <given-names>GD</given-names></name> <name><surname>Wakefield</surname> <given-names>LK</given-names></name> <etal/></person-group>. <article-title>Neuropathology provides clues to the pathophysiology of Gaucher disease</article-title>. <source>Mol Genet Metab</source>. (<year>2004</year>) <volume>82</volume>:<fpage>192</fpage>&#x2013;<lpage>207</lpage>. doi: <pub-id pub-id-type="doi">10.1016/j.ymgme.2004.04.011</pub-id></citation></ref>
<ref id="ref57"><label>57.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Farrer</surname> <given-names>MJ</given-names></name> <name><surname>Williams</surname> <given-names>LN</given-names></name> <name><surname>Algom</surname> <given-names>AA</given-names></name> <name><surname>Kachergus</surname> <given-names>J</given-names></name> <name><surname>Hulihan</surname> <given-names>MM</given-names></name> <name><surname>Ross</surname> <given-names>OA</given-names></name> <etal/></person-group>. <article-title>Glucosidase-beta variations and Lewy body disorders</article-title>. <source>Parkinsonism Relat Disord</source>. (<year>2009</year>) <volume>15</volume>:<fpage>414</fpage>&#x2013;<lpage>6</lpage>. doi: <pub-id pub-id-type="doi">10.1016/j.parkreldis.2008.08.004</pub-id></citation></ref>
<ref id="ref58"><label>58.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Neumann</surname> <given-names>J</given-names></name> <name><surname>Bras</surname> <given-names>J</given-names></name> <name><surname>Deas</surname> <given-names>E</given-names></name> <name><surname>O'Sullivan</surname> <given-names>SS</given-names></name> <name><surname>Parkkinen</surname> <given-names>L</given-names></name> <name><surname>Lachmann</surname> <given-names>RH</given-names></name> <etal/></person-group>. <article-title>Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease</article-title>. <source>Brain</source>. (<year>2009</year>) <volume>132</volume>:<fpage>1783</fpage>&#x2013;<lpage>94</lpage>. doi: <pub-id pub-id-type="doi">10.1093/brain/awp044</pub-id>, PMID: <pub-id pub-id-type="pmid">19286695</pub-id></citation></ref>
<ref id="ref59"><label>59.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Mata</surname> <given-names>IF</given-names></name> <name><surname>Samii</surname> <given-names>A</given-names></name> <name><surname>Schneer</surname> <given-names>SH</given-names></name> <name><surname>Roberts</surname> <given-names>JW</given-names></name> <name><surname>Griffith</surname> <given-names>A</given-names></name> <name><surname>Leis</surname> <given-names>BC</given-names></name> <etal/></person-group>. <article-title>Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders</article-title>. <source>Arch Neurol</source>. (<year>2008</year>) <volume>65</volume>:<fpage>379</fpage>&#x2013;<lpage>82</lpage>. doi: <pub-id pub-id-type="doi">10.1001/archneurol.2007.68</pub-id>, PMID: <pub-id pub-id-type="pmid">18332251</pub-id></citation></ref>
<ref id="ref60"><label>60.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Michael</surname> <given-names>J</given-names></name> <name><surname>Eblan</surname> <given-names>JMW</given-names></name> <name><surname>Sidransky</surname> <given-names>E</given-names></name></person-group>. <article-title>The glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews</article-title>. <source>N Engl J Med</source>. (<year>2005</year>) <volume>352</volume>:<fpage>728</fpage>&#x2013;<lpage>31</lpage>. doi: <pub-id pub-id-type="doi">10.1056/NEJM200502173520719</pub-id></citation></ref>
<ref id="ref61"><label>61.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lwin</surname> <given-names>A</given-names></name> <name><surname>Orvisky</surname> <given-names>E</given-names></name> <name><surname>Goker-Alpan</surname> <given-names>O</given-names></name> <name><surname>LaMarca</surname> <given-names>ME</given-names></name> <name><surname>Sidransky</surname> <given-names>E</given-names></name></person-group>. <article-title>Glucocerebrosidase mutations in subjects with parkinsonism</article-title>. <source>Mol Genet Metab</source>. (<year>2004</year>) <volume>81</volume>:<fpage>70</fpage>&#x2013;<lpage>3</lpage>. doi: <pub-id pub-id-type="doi">10.1016/j.ymgme.2003.11.004</pub-id></citation></ref>
<ref id="ref62"><label>62.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Taipa</surname> <given-names>R</given-names></name> <name><surname>Pereira</surname> <given-names>C</given-names></name> <name><surname>Reis</surname> <given-names>I</given-names></name> <name><surname>Alonso</surname> <given-names>I</given-names></name> <name><surname>Bastos-Lima</surname> <given-names>A</given-names></name> <name><surname>Melo-Pires</surname> <given-names>M</given-names></name> <etal/></person-group>. <article-title>DJ-1 linked parkinsonism (PARK7) is associated with Lewy body pathology</article-title>. <source>Brain</source>. (<year>2016</year>) <volume>139</volume>:<fpage>1680</fpage>&#x2013;<lpage>7</lpage>. doi: <pub-id pub-id-type="doi">10.1093/brain/aww080</pub-id>, PMID: <pub-id pub-id-type="pmid">27085187</pub-id></citation></ref>
<ref id="ref63"><label>63.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Sharp</surname> <given-names>ME</given-names></name> <name><surname>Marder</surname> <given-names>KS</given-names></name> <name><surname>Cote</surname> <given-names>L</given-names></name> <name><surname>Clark</surname> <given-names>LN</given-names></name> <name><surname>Nichols</surname> <given-names>WC</given-names></name> <name><surname>Vonsattel</surname> <given-names>JP</given-names></name> <etal/></person-group>. <article-title>Parkinson's disease with Lewy bodies associated with a heterozygous PARKIN dosage mutation</article-title>. <source>Mov Disord</source>. (<year>2014</year>) <volume>29</volume>:<fpage>566</fpage>&#x2013;<lpage>8</lpage>. doi: <pub-id pub-id-type="doi">10.1002/mds.25792</pub-id>, PMID: <pub-id pub-id-type="pmid">24375549</pub-id></citation></ref>
<ref id="ref64"><label>64.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Farrer</surname> <given-names>M</given-names></name> <name><surname>Chan</surname> <given-names>P</given-names></name> <name><surname>Chen</surname> <given-names>R</given-names></name> <name><surname>Tan</surname> <given-names>L</given-names></name> <name><surname>Lincoln</surname> <given-names>S</given-names></name> <name><surname>Hernandez</surname> <given-names>D</given-names></name> <etal/></person-group>. <article-title>Lewy bodies and parkinsonism in families with parkin mutations</article-title>. <source>Ann Neurol</source>. (<year>2001</year>) <volume>50</volume>:<fpage>293</fpage>&#x2013;<lpage>300</lpage>. doi: <pub-id pub-id-type="doi">10.1002/ana.1132</pub-id>, PMID: <pub-id pub-id-type="pmid">11558785</pub-id></citation></ref>
<ref id="ref65"><label>65.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ruffmann</surname> <given-names>C</given-names></name> <name><surname>Zini</surname> <given-names>M</given-names></name> <name><surname>Goldwurm</surname> <given-names>S</given-names></name> <name><surname>Bramerio</surname> <given-names>M</given-names></name> <name><surname>Spinello</surname> <given-names>S</given-names></name> <name><surname>Rusconi</surname> <given-names>D</given-names></name> <etal/></person-group>. <article-title>Lewy body pathology and typical Parkinson disease in a patient with a heterozygous (R275W) mutation in the Parkin gene (PARK2)</article-title>. <source>Acta Neuropathol</source>. (<year>2012</year>) <volume>123</volume>:<fpage>901</fpage>&#x2013;<lpage>3</lpage>. doi: <pub-id pub-id-type="doi">10.1007/s00401-012-0991-7</pub-id></citation></ref>
<ref id="ref66"><label>66.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Doherty</surname> <given-names>KM</given-names></name> <name><surname>Silveira-Moriyama</surname> <given-names>L</given-names></name> <name><surname>Parkkinen</surname> <given-names>L</given-names></name> <name><surname>Healy</surname> <given-names>DG</given-names></name> <name><surname>Farrell</surname> <given-names>M</given-names></name> <name><surname>Mencacci</surname> <given-names>NE</given-names></name> <etal/></person-group>. <article-title>Parkin disease: a clinicopathologic entity?</article-title> <source>JAMA Neurol</source>. (<year>2013</year>) <volume>70</volume>:<fpage>571</fpage>&#x2013;<lpage>9</lpage>. doi: <pub-id pub-id-type="doi">10.1001/jamaneurol.2013.172</pub-id>, PMID: <pub-id pub-id-type="pmid">23459986</pub-id></citation></ref>
<ref id="ref67"><label>67.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Sasaki</surname> <given-names>SSA</given-names></name> <name><surname>Yamane</surname> <given-names>K</given-names></name> <name><surname>Iwata</surname> <given-names>M</given-names></name></person-group>. <article-title>Parkin-positive autosomal recessive juvenile parkinsonism with a synuclein positive inclusions</article-title>. <source>Neurology</source>. (<year>2004</year>) <volume>63</volume>:<fpage>678</fpage>&#x2013;<lpage>82</lpage>. doi: <pub-id pub-id-type="doi">10.1212/01.WNL.0000134657.25904.0B</pub-id>, PMID: <pub-id pub-id-type="pmid">15326242</pub-id></citation></ref>
<ref id="ref68"><label>68.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Seike</surname> <given-names>N</given-names></name> <name><surname>Yokoseki</surname> <given-names>A</given-names></name> <name><surname>Takeuchi</surname> <given-names>R</given-names></name> <name><surname>Saito</surname> <given-names>K</given-names></name> <name><surname>Miyahara</surname> <given-names>H</given-names></name> <name><surname>Miyashita</surname> <given-names>A</given-names></name> <etal/></person-group>. <article-title>Genetic variations and Neuropathologic features of patients with PRKN mutations</article-title>. <source>Mov Disord</source>. (<year>2021</year>) <volume>36</volume>:<fpage>1634</fpage>&#x2013;<lpage>43</lpage>. doi: <pub-id pub-id-type="doi">10.1002/mds.28521</pub-id></citation></ref>
<ref id="ref69"><label>69.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Doppler</surname> <given-names>K</given-names></name> <name><surname>Ebert</surname> <given-names>S</given-names></name> <name><surname>Uceyler</surname> <given-names>N</given-names></name> <name><surname>Trenkwalder</surname> <given-names>C</given-names></name> <name><surname>Ebentheuer</surname> <given-names>J</given-names></name> <name><surname>Volkmann</surname> <given-names>J</given-names></name> <etal/></person-group>. <article-title>Cutaneous neuropathy in Parkinson's disease: a window into brain pathology</article-title>. <source>Acta Neuropathol</source>. (<year>2014</year>) <volume>128</volume>:<fpage>99</fpage>&#x2013;<lpage>109</lpage>. doi: <pub-id pub-id-type="doi">10.1007/s00401-014-1284-0</pub-id>, PMID: <pub-id pub-id-type="pmid">24788821</pub-id></citation></ref>
<ref id="ref70"><label>70.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Vazquez-Velez</surname> <given-names>GE</given-names></name> <name><surname>Zoghbi</surname> <given-names>HY</given-names></name></person-group>. <article-title>Parkinson's disease genetics and pathophysiology</article-title>. <source>Annu Rev Neurosci</source>. (<year>2021</year>) <volume>44</volume>:<fpage>87</fpage>&#x2013;<lpage>108</lpage>. doi: <pub-id pub-id-type="doi">10.1146/annurev-neuro-100720-034518</pub-id></citation></ref>
<ref id="ref71"><label>71.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Andreasson</surname> <given-names>M</given-names></name> <name><surname>Svenningsson</surname> <given-names>P</given-names></name></person-group>. <article-title>Update on alpha-synuclein-based biomarker approaches in the skin, submandibular gland, gastrointestinal tract, and biofluids</article-title>. <source>Curr Opin Neurol</source>. (<year>2021</year>) <volume>34</volume>:<fpage>572</fpage>&#x2013;<lpage>7</lpage>. doi: <pub-id pub-id-type="doi">10.1097/WCO.0000000000000948</pub-id>, PMID: <pub-id pub-id-type="pmid">33967199</pub-id></citation></ref>
<ref id="ref72"><label>72.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Chahine</surname> <given-names>LM</given-names></name> <name><surname>Beach</surname> <given-names>TG</given-names></name> <name><surname>Brumm</surname> <given-names>MC</given-names></name> <name><surname>Adler</surname> <given-names>CH</given-names></name> <name><surname>Coffey</surname> <given-names>CS</given-names></name> <name><surname>Mosovsky</surname> <given-names>S</given-names></name> <etal/></person-group>. <article-title>In vivo distribution of alpha-synuclein in multiple tissues and biofluids in Parkinson disease</article-title>. <source>Neurology</source>. (<year>2020</year>) <volume>95</volume>:<fpage>e1267</fpage>&#x2013;<lpage>84</lpage>. doi: <pub-id pub-id-type="doi">10.1212/WNL.0000000000010404</pub-id>, PMID: <pub-id pub-id-type="pmid">32747521</pub-id></citation></ref>
<ref id="ref73"><label>73.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Hustad</surname> <given-names>E</given-names></name> <name><surname>Aasly</surname> <given-names>JO</given-names></name></person-group>. <article-title>Clinical and imaging markers of prodromal Parkinson's disease</article-title>. <source>Front Neurol</source>. (<year>2020</year>) <volume>11</volume>:<fpage>395</fpage>. doi: <pub-id pub-id-type="doi">10.3389/fneur.2020.00395</pub-id>, PMID: <pub-id pub-id-type="pmid">32457695</pub-id></citation></ref>
<ref id="ref74"><label>74.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Mangone</surname> <given-names>G</given-names></name> <name><surname>Houot</surname> <given-names>M</given-names></name> <name><surname>Gaurav</surname> <given-names>R</given-names></name> <name><surname>Boluda</surname> <given-names>S</given-names></name> <name><surname>Pyatigorskaya</surname> <given-names>N</given-names></name> <name><surname>Chalancon</surname> <given-names>A</given-names></name> <etal/></person-group>. <article-title>Relationship between substantia Nigra Neuromelanin imaging and dual alpha-Synuclein labeling of labial minor in salivary glands in isolated rapid eye movement sleep behavior disorder and Parkinson&#x2019;s disease</article-title>. <source>Genes</source>. (<year>2022</year>) <volume>13</volume>:<fpage>1715</fpage>. doi: <pub-id pub-id-type="doi">10.3390/genes13101715</pub-id>, PMID: <pub-id pub-id-type="pmid">36292600</pub-id></citation></ref>
<ref id="ref75"><label>75.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Harapan</surname> <given-names>BN</given-names></name> <name><surname>Frydrychowicz</surname> <given-names>C</given-names></name> <name><surname>Classen</surname> <given-names>J</given-names></name> <name><surname>Wittekind</surname> <given-names>C</given-names></name> <name><surname>Gradistanac</surname> <given-names>T</given-names></name> <name><surname>Rumpf</surname> <given-names>JJ</given-names></name> <etal/></person-group>. <article-title>No enhanced (p-) alpha-synuclein deposition in gastrointestinal tissue of Parkinson's disease patients</article-title>. <source>Parkinsonism Relat Disord</source>. (<year>2020</year>) <volume>80</volume>:<fpage>82</fpage>&#x2013;<lpage>8</lpage>. doi: <pub-id pub-id-type="doi">10.1016/j.parkreldis.2020.08.020</pub-id>, PMID: <pub-id pub-id-type="pmid">32971383</pub-id></citation></ref>
<ref id="ref76"><label>76.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Adler</surname> <given-names>CH</given-names></name> <name><surname>Serrano</surname> <given-names>GE</given-names></name> <name><surname>Zhang</surname> <given-names>N</given-names></name> <name><surname>Hinni</surname> <given-names>ML</given-names></name> <name><surname>Lott</surname> <given-names>DG</given-names></name> <name><surname>Mehta</surname> <given-names>SH</given-names></name> <etal/></person-group>. <article-title>Feasibility of repeat and bilateral submandibular gland needle biopsies in Parkinson's disease</article-title>. <source>Parkinsonism Relat Disord</source>. (<year>2019</year>) <volume>68</volume>:<fpage>69</fpage>&#x2013;<lpage>72</lpage>. doi: <pub-id pub-id-type="doi">10.1016/j.parkreldis.2019.10.006</pub-id>, PMID: <pub-id pub-id-type="pmid">31621624</pub-id></citation></ref>
<ref id="ref77"><label>77.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Liu</surname> <given-names>X</given-names></name> <name><surname>Yang</surname> <given-names>J</given-names></name> <name><surname>Yuan</surname> <given-names>Y</given-names></name> <name><surname>He</surname> <given-names>Q</given-names></name> <name><surname>Gao</surname> <given-names>Y</given-names></name> <name><surname>Jiang</surname> <given-names>C</given-names></name> <etal/></person-group>. <article-title>Optimization of the detection method for phosphorylated alpha-Synuclein in Parkinson disease by skin biopsy</article-title>. <source>Front Neurol</source>. (<year>2020</year>) <volume>11</volume>:<fpage>569446</fpage>. doi: <pub-id pub-id-type="doi">10.3389/fneur.2020.569446</pub-id>, PMID: <pub-id pub-id-type="pmid">33101177</pub-id></citation></ref>
<ref id="ref78"><label>78.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname> <given-names>N</given-names></name> <name><surname>Gibbons</surname> <given-names>CH</given-names></name> <name><surname>Lafo</surname> <given-names>J</given-names></name> <name><surname>Freeman</surname> <given-names>R</given-names></name></person-group>. <article-title>&#x03B1;-Synuclein in cutaneous autonomic nerves</article-title>. <source>Neurology</source>. (<year>2013</year>) <volume>81</volume>:<fpage>1604</fpage>&#x2013;<lpage>10</lpage>. doi: <pub-id pub-id-type="doi">10.1212/WNL.0b013e3182a9f449</pub-id>, PMID: <pub-id pub-id-type="pmid">24089386</pub-id></citation></ref>
<ref id="ref79"><label>79.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Horsager</surname> <given-names>J</given-names></name> <name><surname>Knudsen</surname> <given-names>K</given-names></name> <name><surname>Sommerauer</surname> <given-names>M</given-names></name></person-group>. <article-title>Clinical and imaging evidence of brain-first and body-first Parkinson's disease</article-title>. <source>Neurobiol Dis</source>. (<year>2022</year>) <volume>164</volume>:<fpage>105626</fpage>. doi: <pub-id pub-id-type="doi">10.1016/j.nbd.2022.105626</pub-id>, PMID: <pub-id pub-id-type="pmid">35031485</pub-id></citation></ref>
<ref id="ref80"><label>80.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Fearon</surname> <given-names>C</given-names></name> <name><surname>Lang</surname> <given-names>AE</given-names></name> <name><surname>Espay</surname> <given-names>AJ</given-names></name></person-group>. <article-title>The logic and pitfalls of Parkinson's disease as &#x201C;brain-first&#x201D; versus &#x201C;body-first&#x201D; subtypes</article-title>. <source>Mov Disord</source>. (<year>2021</year>) <volume>36</volume>:<fpage>594</fpage>&#x2013;<lpage>8</lpage>. doi: <pub-id pub-id-type="doi">10.1002/mds.28493</pub-id>, PMID: <pub-id pub-id-type="pmid">33749922</pub-id></citation></ref>
<ref id="ref81"><label>81.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Schneider</surname> <given-names>SA</given-names></name> <name><surname>Alcalay</surname> <given-names>RN</given-names></name></person-group>. <article-title>Neuropathology of genetic synucleinopathies with parkinsonism: review of the literature</article-title>. <source>Mov Disord</source>. (<year>2017</year>) <volume>32</volume>:<fpage>1504</fpage>&#x2013;<lpage>23</lpage>. doi: <pub-id pub-id-type="doi">10.1002/mds.27193</pub-id>, PMID: <pub-id pub-id-type="pmid">29124790</pub-id></citation></ref>
<ref id="ref82"><label>82.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Cookson</surname> <given-names>MR</given-names></name> <name><surname>Lockhart</surname> <given-names>PJ</given-names></name> <name><surname>McLendon</surname> <given-names>C</given-names></name> <name><surname>O'Farrell</surname> <given-names>C</given-names></name> <name><surname>Schlossmacher</surname> <given-names>M</given-names></name> <name><surname>Farrer</surname> <given-names>MJ</given-names></name></person-group>. <article-title>RING finger 1 mutations in Parkin produce altered localization of the protein</article-title>. <source>Hum Mol Genet</source>. (<year>2003</year>) <volume>12</volume>:<fpage>2957</fpage>&#x2013;<lpage>65</lpage>. doi: <pub-id pub-id-type="doi">10.1093/hmg/ddg328</pub-id>, PMID: <pub-id pub-id-type="pmid">14519684</pub-id></citation></ref>
<ref id="ref83"><label>83.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Sun</surname> <given-names>Q</given-names></name> <name><surname>Wang</surname> <given-names>T</given-names></name> <name><surname>Jiang</surname> <given-names>TF</given-names></name> <name><surname>Huang</surname> <given-names>P</given-names></name> <name><surname>Li</surname> <given-names>DH</given-names></name> <name><surname>Wang</surname> <given-names>Y</given-names></name> <etal/></person-group>. <article-title>Effect of a leucine-rich repeat kinase 2 variant on motor and non-motor symptoms in Chinese Parkinson's disease patients</article-title>. <source>Aging Dis</source>. (<year>2016</year>) <volume>7</volume>:<fpage>230</fpage>&#x2013;<lpage>6</lpage>. doi: <pub-id pub-id-type="doi">10.14336/AD.2015.1026</pub-id>, PMID: <pub-id pub-id-type="pmid">27330837</pub-id></citation></ref>
<ref id="ref84"><label>84.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Rossi</surname> <given-names>M</given-names></name> <name><surname>Candelise</surname> <given-names>N</given-names></name> <name><surname>Baiardi</surname> <given-names>S</given-names></name> <name><surname>Capellari</surname> <given-names>S</given-names></name> <name><surname>Giannini</surname> <given-names>G</given-names></name> <name><surname>Orr&#x00F9;</surname> <given-names>CD</given-names></name> <etal/></person-group>. <article-title>Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies</article-title>. <source>Acta Neuropathol</source>. (<year>2020</year>) <volume>140</volume>:<fpage>49</fpage>&#x2013;<lpage>62</lpage>. doi: <pub-id pub-id-type="doi">10.1007/s00401-020-02160-8</pub-id>, PMID: <pub-id pub-id-type="pmid">32342188</pub-id></citation></ref>
<ref id="ref85"><label>85.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Pezzoli</surname> <given-names>G</given-names></name> <name><surname>Cappelletti</surname> <given-names>G</given-names></name> <name><surname>Cilia</surname> <given-names>R</given-names></name> <name><surname>Sacilotto</surname> <given-names>G</given-names></name> <name><surname>De Leonardis</surname> <given-names>M</given-names></name> <name><surname>Bolliri</surname> <given-names>C</given-names></name> <etal/></person-group>. <article-title>&#x03B1;-Synuclein oligomers in skin biopsy of idiopathic and monozygotic twin patients with Parkinson&#x2019;s disease</article-title>. <source>Brain</source>. (<year>2020</year>) <volume>143</volume>:<fpage>920</fpage>&#x2013;<lpage>31</lpage>. doi: <pub-id pub-id-type="doi">10.1093/brain/awaa008</pub-id></citation></ref>
<ref id="ref86"><label>86.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Chu</surname> <given-names>Y</given-names></name> <name><surname>Hirst</surname> <given-names>WD</given-names></name> <name><surname>Federoff</surname> <given-names>HJ</given-names></name> <name><surname>Harms</surname> <given-names>AS</given-names></name> <name><surname>Stoessl</surname> <given-names>AJ</given-names></name> <name><surname>Kordower</surname> <given-names>JH</given-names></name></person-group>. <article-title>Nigrostriatal tau pathology in parkinsonism and Parkinson&#x2019;s disease</article-title>. <source>Brain</source>. (<year>2024</year>) <volume>147</volume>:<fpage>444</fpage>&#x2013;<lpage>57</lpage>. doi: <pub-id pub-id-type="doi">10.1093/brain/awad388</pub-id>, PMID: <pub-id pub-id-type="pmid">38006313</pub-id></citation></ref>
<ref id="ref87"><label>87.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Vacchi</surname> <given-names>E</given-names></name> <name><surname>Lazzarini</surname> <given-names>E</given-names></name> <name><surname>Pinton</surname> <given-names>S</given-names></name> <name><surname>Chiaro</surname> <given-names>G</given-names></name> <name><surname>Disanto</surname> <given-names>G</given-names></name> <name><surname>Marchi</surname> <given-names>F</given-names></name> <etal/></person-group>. <article-title>Tau protein quantification in skin biopsies differentiates tauopathies from alpha-synucleinopathies</article-title>. <source>Brain</source>. (<year>2022</year>) <volume>145</volume>:<fpage>2755</fpage>&#x2013;<lpage>68</lpage>. doi: <pub-id pub-id-type="doi">10.1093/brain/awac161</pub-id>, PMID: <pub-id pub-id-type="pmid">35485527</pub-id></citation></ref>
<ref id="ref88"><label>88.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Garrido</surname> <given-names>A</given-names></name> <name><surname>Fairfoul</surname> <given-names>G</given-names></name> <name><surname>Tolosa</surname> <given-names>E</given-names></name> <name><surname>Marti</surname> <given-names>M</given-names></name> <name><surname>Ezquerra</surname> <given-names>M</given-names></name> <name><surname>Green</surname> <given-names>A</given-names></name></person-group>. <article-title>Brain and cerebrospinal fluid &#x03B1;-Synuclein real-time quaking-induced conversion identifies Lewy body pathology in LRRK2-PD</article-title>. <source>Mov Disord</source>. (<year>2023</year>) <volume>38</volume>:<fpage>333</fpage>&#x2013;<lpage>8</lpage>. doi: <pub-id pub-id-type="doi">10.1002/mds.29284</pub-id>, PMID: <pub-id pub-id-type="pmid">36471633</pub-id></citation></ref>
<ref id="ref89"><label>89.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Simuni</surname> <given-names>T</given-names></name> <name><surname>Chahine</surname> <given-names>L</given-names></name> <name><surname>Poston</surname> <given-names>K</given-names></name> <name><surname>Brumm</surname> <given-names>M</given-names></name> <name><surname>Buracchio</surname> <given-names>T</given-names></name> <name><surname>Campbell</surname> <given-names>M</given-names></name> <etal/></person-group>. <article-title>A biological definition of neuronal &#x03B1;-synuclein disease: towards an integrated staging system for research</article-title>. <source>Lancet Neurol</source>. (<year>2024</year>) <volume>23</volume>:<fpage>178</fpage>&#x2013;<lpage>90</lpage>. doi: <pub-id pub-id-type="doi">10.1016/S1474-4422(23)00405-2</pub-id>, PMID: <pub-id pub-id-type="pmid">38267190</pub-id></citation></ref>
<ref id="ref90"><label>90.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>H&#x00F6;glinger</surname> <given-names>G</given-names></name> <name><surname>Adler</surname> <given-names>C</given-names></name> <name><surname>Berg</surname> <given-names>D</given-names></name> <name><surname>Klein</surname> <given-names>C</given-names></name> <name><surname>Outeiro</surname> <given-names>T</given-names></name> <name><surname>Poewe</surname> <given-names>W</given-names></name> <etal/></person-group>. <article-title>A biological classification of Parkinson's disease: the SynNeurGe research diagnostic criteria</article-title>. <source>Lancet Neurol</source>. (<year>2024</year>) <volume>23</volume>:<fpage>191</fpage>&#x2013;<lpage>204</lpage>. doi: <pub-id pub-id-type="doi">10.1016/S1474-4422(23)00404-0</pub-id>, PMID: <pub-id pub-id-type="pmid">38267191</pub-id></citation></ref>
</ref-list>
</back></article>