α‐Synuclein Deposition in Sympathetic Nerve Fibers in Genetic Forms of Parkinson's Disease

Abstract

A BS TRACT: Background: Cytoplasmic inclusions of α-synuclein (α-syn) in brainstem neurons are characteristic of idiopathic Parkinson's disease (PD). PD also entails α-syn buildup in sympathetic nerves. Among genetic forms of PD, the relative extents of sympathetic intraneuronal accumulation of α-syn have not been reported. Objective: This cross-sectional observational study compared magnitudes of intraneuronal deposition of α-syn in common and rare genetic forms of PD. Methods: α-Syn deposition was quantified by the α-syntyrosine 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: α-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. α-Syn deposition in the biallelic PRKN group was significantly higher than in the control group. In addition, patients with biallelic PRKN mutations had higher α-syn deposition than their unaffected siblings. Conclusions: Individuals with SNCA, DJ-1, LRRK2, or GBA mutations have substantial intraneuronal α-syn deposition in sympathetic noradrenergic nerves in skin biopsies, whereas those with biallelic PRKN mutations do not. Biallelic PRKN patients may have mildly increased α-syn deposition compared with control subjects.

Skin alpha-synuclein deposit patterns: A predictor of Parkinson's disease subtypes

“…The results showed significantly more intraneuronal total α-syn depositions in skin sympathetic noradrenergic nerve fibers of PD patients with LRRK2 mutations compared to controls. 35 Total α-syn comprises the different elements from p-α-syn in the pathology, and numerous Lewy body and neurite like accumulations of α-syn along with a diffuse neuropil signal were found when staining for total α-syn (syn211) in PD brains. 10 We assume that staining for total α-syn and p-α-syn are both meaningful.…”

“…An increasing number of studies have examined the role and contribution of genetic factors in familial and sporadic PD (sPD), concluding that a significant source of PD risk is genetic. 35 Nalls et al. identified 90 independent genome-wide significant risk signals by meta-analysis, including the common risk variants leucine-rich repeat kinase 2 ( LRRK2 ), glucocerebrosidase ( GBA ), and SNCA .…”

“…They found that 83% of patients with GBA variants had higher total α-syn deposition in the skin noradrenergic nerves compared to controls. 35 Doppler et al. performed skin biopsy at the distal, proximal leg, paravertebral back Th10, and neck C7 of 10 PD patients with different GBA mutations (6 N370S, 3 E326K, 1 L444P) and 10 healthy controls.…”

“…performed C2 cervical skin biopsies of 2 PD patients with SNCA mutations and 16 control participants, and found that total α-syn deposition in noradrenergic nerves was higher in PD patients compared to controls. 35 …”

Diagnosis and Treatment of Essential Tremor

“…42 In recent times, measuring phosphorylated α-synuclein in CSF or peripheral tissue, such as a skin biopsy, has been described in patients with Parkinson disease and might be useful in distinguishing patients with Parkinson disease tremor from those with essential tremor. 43 However, the accuracy, sensitivity, specificity, and the optimal tissue analysis technique will require more studies before a broader implementation in clinical practice.…”