AUTHOR=Yuan Yanpeng , Wang Yangyang , Liu Minglei , Luo Haiyang , Liu Xiaojing , Li Lanjun , Mao Chengyuan , Yang Ting , Li Shuo , Zhang Xiaoyun , Gao Yuan , Xu Yuming , Yang Jing 

TITLE=Peripheral cutaneous synucleinopathy characteristics in genetic Parkinson’s disease

JOURNAL=Frontiers in Neurology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2024.1404492

DOI=10.3389/fneur.2024.1404492

ISSN=1664-2295

ABSTRACT=<sec id="sec1"><title>Background</title><p>Cutaneous phosphorylated alpha-synuclein (p-α-syn) deposition is an important biomarker of idiopathic Parkinson’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-α-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-α-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 α-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 α-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-α-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>