Objective: To investigate the correlation of somatic copy number variants (CNVs) of the alpha-synuclein gene (SNCA) in multiple system atrophy (MSA) with disease subtype, and with the presence of inclusions.

Background: Somatic mutations, which occur post-zygotically and lead to mosaicism, may have a role in sporadic synucleinopathies. We previously reported somatic SNCA CNVs (gains) in substantia nigra (SN) and cingulate cortex of MSA and Parkinson’s disease using fluorescent in situ hybridisation (FISH).

Method: We performed FISH for SNCA copy numbers on brain sections, combined with immunofluorescence for alpha-synuclein to detect inclusions, and in some cases also TPPP, an oligodendrocyte protein which may enhance α-synuclein aggregation.

Results: We compared the MSA subtypes of striatonigral degeneration (SND) and olivopontocerebellar atrophy (OPCA). We first investigated whether mosaicism in a given brain region differs based on the involvement of the region in each MSA subtype by studying putaminal striatopallidal fibres, cerebellar white matter, and substantia nigra (SN). We analysed at least one of these from 24 MSA cases (11 SND, 13 OPCA), We found that in a region preferentially affected in one MSA subtype, mosaicism is higher in that subtype: putamen in SND, and cerebellum in OPCA. In the SN, affected in both, we saw no difference.
We next investigated whether alpha-synuclein inclusions occur preferentially in cells with CNVs. In the cerebellum, cells with CNVs were 4.2x more likely to have inclusions in OPCA, and 2.7x more likely in SND, while in the putamen, cells with CNVs were 4.2x more likely to have inclusions in SND. We conclude that CNVs are associated with inclusions in the same cells in affected regions. In the SN, non-pigmented cells with CNVs were ~6x more likely to have inclusions in both subtypes, if they also expressed TPPP. This suggests that an oligodendrocyte with both a CNV and TPPP expression may be most likely to develop inclusions.

Conclusion: We provide the first evidence in MSA, and to our knowledge in any neurodegenerative disorder, that the level of a relevant somatic mutation in a brain region is higher in the disease subtype where it is preferentially affected. The association between CNVs and inclusions in the same cells in affected regions suggest that CNVs may be causal, especially in cells withconcomitant TPPP expression.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/mosaicism-for-somatic-snca-copy-number-variants-in-multiple-system-atrophy-is-related-to-pathological-subtype-and-presence-of-%ce%b1-synuclein-inclusions/