alpha-Synuclein Deposition in Sympathetic Nerve Fibers in Genetic Forms of Parkinson's Disease

Background: Cytoplasmic inclusions of alpha-synuclein (alpha-syn) in brainstem neurons are characteristic of idiopathic Parkinson's disease (PD). PD also entails alpha-syn buildup in sympathetic nerves. Among genetic forms of PD, the relative extents of sympathetic intraneuronal accumulation of alpha-syn have not been reported. Objective: This cross-sectional observational study compared magnitudes of intraneuronal deposition of alpha-syn in common and rare genetic forms of PD. Methods: alpha-Syn deposition was quantified by the alpha-syn-tyrosine hydroxylase colocalization index in C2 cervical skin biopsies from 65 subjects. These included 30 subjects with pathogenic mutations in SNCA (n = 3), PRKN [biallelic (n = 7) and monoallelic (n = 3)], LRRK2 (n = 7), GBA (n = 7), or PARK7/DJ1 [biallelic (n = 1) and monoallelic (n = 2)]. Twenty-five of the mutation carriers had PD and five did not. Data were also analyzed from 19 patients with idiopathic PD and 16 control participants. Results: alpha-Syn deposition varied as a function of genotype (F = 16.7, P < 0.0001). It was above the control range in 100% of subjects with SNCA mutations, 100% with LRRK2 mutations, 95% with idiopathic PD, 83% with GBA mutations, and 0% with biallelic PRKN mutations. alpha-Syn deposition in the biallelic PRKN group was significantly higher than in the control group. In addition, patients with biallelic PRKN mutations had higher alpha-syn deposition than their unaffected siblings. Conclusions: Individuals with SNCA, DJ-1, LRRK2, or GBA mutations have substantial intraneuronal alpha-syn deposition in sympathetic noradrenergic nerves in skin biopsies, whereas those with biallelic PRKN mutations do not. Biallelic PRKN patients may have mildly increased alpha-syn deposition compared with control subjects. (c) 2021 International Parkinson and Movement Disorder Society