Somatic SNCA Copy Number Variants in Multiple System Atrophy are Related to Pathology and Inclusions |
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| Authors: | Monica Emili Garcia-Segura Diego Perez-Rodriguez PhD Darren Chambers Zane Jaunmuktane Christos Proukakis PhD FRCP |
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| Affiliation: | 1. Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK;2. The Dubowitz Neuromuscular Centre, Division of Neuropathology, UCL Queen Square Institute of Neurology, University College London, London, UK |
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| Abstract: | Background Somatic α-synuclein (SNCA) copy number variants (CNVs, specifically gains) occur in multiple system atrophy (MSA) and Parkinson's disease brains. Objective The aim was to compare somatic SNCA CNVs in MSA subtypes (striatonigral degeneration [SND] and olivopontocerebellar atrophy [OPCA]) and correlate with inclusions. Methods We combined fluorescent in situ hybridization with immunofluorescence for α-synuclein and in some cases oligodendrocyte marker tubulin polymerization promoting protein (TPPP). Results We analyzed one to three brain regions from 24 MSA cases (13 SND, 11 OPCA). In a region preferentially affected in one subtype (putamen in SND, cerebellum in OPCA), mosaicism was higher in that subtype, and cells with CNVs were 4.2 times more likely to have inclusions. In the substantia nigra, nonpigmented cells with CNVs and TPPP were about six times more likely to have inclusions. Conclusions The correlation between SNCA CNVs and pathology (at a regional level) and inclusions (at a single-cell level) suggests a role for somatic SNCA CNVs in MSA pathogenesis. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. |
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| Keywords: | snca alpha-synuclein mosaicism multiple system atrophy somatic mutation |
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