Objective: To compare α-synuclein oligomers and synaptic density (SD) in skin biopsies from PD and GBA-PD.

Background: Previous research [1] reported α-synuclein oligomers within synaptic terminals of autonomic fibers in skin biopsies from idiopathic Parkinson’s disease (PD) patients employing the proximity ligation assay (PLA), but no information in glucocerebrosidase (GBA)-mutated PD is available.

Method: We collected genetic and clinical data and skin biopsies in 35 patients with PD and 27 with GBA-PD (7 with N370S, 12 with L444P, 8 with compound heterozygous/homozygous mutations or other risk variants). Quantitative analysis was conducted in all the samples containing the sweat gland, which displayed the greatest quantity of autonomic synaptic terminals. The SD was calculated as the ratio between total synaptic terminals and the area of the sweat gland [2], and the α-synuclein oligomers were quantified as the area of PLA signal within synapses normalized for SD.

Results: GBA-PD were younger, had an earlier age at PD onset, and had longer disease duration compared with PD. Orthostatic hypotension was reported in 25.9% of GBA-PD and 20% of PD (p=0.23). No difference in PLA score could be detected between GBA-PD and PD, as well as between different GBA-PD subgroups. Concerning SD, significantly higher values were found in GBA-PD than PD (p<0.001). After controlling in multivariate regression analysis for the effect of age, sex, disease duration, UPDRS-III scores, and Hoehn and Yahr stage, the effect of genetic status was confirmed as a predictor for SD (beta=0.645, 95% CI 0.298-0.752, p<0.001). Interestingly, GBA-PD carrying the N370S mutation displayed higher SD compared with L444P-mutated patients (p=0.05), whereas α-synuclein oligomers did not differ between groups (p=0.8). ROC curve analysis of the SD values showed reliable specificity and sensitivity in detecting GBA-PD (AUC=0.855, p<0.001, sensitivity=85.2%, specificity=77.1%).

Conclusion: The SD values may help to discriminate between GBA-PD and PD.

References: 1. Mazzetti S, Basellini MJ, Ferri V, et al (2020) α-Synuclein oligomers in skin biopsy of idiopathic and monozygotic twin patients with Parkinson’s disease. Brain 143:920–931. doi.org/10.1093/brain/awaa008

2. Navarro-Otano J, Casanova-Mollà J, Morales M, et al (2015) Cutaneous autonomic denervation in Parkinson’s disease. J Neural Transm (Vienna) 122:1149–1155. doi.org/10.1007/s00702-014-1355-3

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MDS Abstracts - https://www.mdsabstracts.org/abstract/synaptic-density-and-%ce%b1-synuclein-oligomers-in-skin-biopsies-differences-between-idiopathic-and-gba-linked-parkinsons-disease/