Peripheral cutaneous synucleinopathy characteristics in genetic Parkinson's disease

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

doi:10.3389/fneur.2024.1404492

Peripheral cutaneous synucleinopathy characteristics in genetic Parkinson's disease

Front Neurol. 2024 May 1:15:1404492. doi: 10.3389/fneur.2024.1404492. eCollection 2024.

Authors

Yanpeng Yuan^#^{1

2

3}, Yangyang Wang^#^{1

2

3}, Minglei Liu¹, Haiyang Luo^{1

2

3

4}, Xiaojing Liu^{1

2

3}, Lanjun Li^{1

2

3}, Chengyuan Mao^{1

2

3

4}, Ting Yang^{1

2

3}, Shuo Li^{1

2

3}, Xiaoyun Zhang¹, Yuan Gao^{1

2

3

4}, Yuming Xu^{1

2

3

4}, Jing Yang^{1

2

3

4}

Affiliations

¹ Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
² Henan Key Laboratory of Cerebrovascular Diseases, Zhengzhou University, Zhengzhou, Henan, China.
³ Institute of Neuroscience, Zhengzhou University, Zhengzhou, Henan, China.
⁴ NHC Key Laboratory of Prevention and Treatment of Cerebrovascular Disease, Zhengzhou, Henan, China.

^# Contributed equally.

Abstract

Background: 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.

Objective: This study aimed to detect p-α-syn deposition characteristic in rare genetic PD patients with CHCHD2 or RAB39B 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.

Methods: We performed four skin biopsy samples from the distal leg (DL) and proximal neck (C7) of 161 participants, including four patients with CHCHD2 mutations, two patients with RAB39B mutations, 16 patients with PRKN mutations, 14 patients with LRRK2 mutations, five patients with GBA 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.

Results: P-α-syn was deposited in the peripheral cutaneous nerves of PD patients with CHCHD2, LRRK2, or GBA mutations but not in those with RAB39B or PRKN 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 LRRK2 and GBA mutation patients revealed prion-like activity.

Conclusion: 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.

Keywords: CHCHD2; RAB39B; SAA; genetic Parkinson’s disease; skin biopsy; α-synuclein.

Grants and funding

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).