Somatic copy number variant mutations in alpha-synuclein and genome-wide in brains of synucleinopathy cases

Abstract

Synucleinopathies are mostly sporadic neurodegenerative disorders, and include Parkinson’s disease (PD), and multiple system atrophy (MSA). Inherited copy number variants (CNVs) ofSNCA(α-synuclein) are rare causes of familial disease. There is increasing evidence for somatic mutations in the human brain, and we have hypothesized a role for these in synucleinopathies.We further investigated somatic CNVs in brains from synucleinopathy cases, using Fluorescent in-situ Hybri- disation forSNCAgains, and single-cell whole genome sequencing for the first time in a synucleinopathy. In the cingulate cortex, mosaicism forSNCAgains was higher in MSA and PD than controls in neurons (> 2% in both diseases), and for MSA also in non-neurons. In MSA substantia nigra (SN), we notedSNCAgains in> 3% of cells. Cells with CNVs were more likely to have α-synuclein inclusions, in a pattern corresponding to cell categories mostly relevant to the disease: dopaminergic neurons in Lewy-body cases, and other cells in striatonigral degeneration-dominant MSA (MSA-SND). HigherSNCACNV mosaicism in typical MSA-SND SN non-dopaminergic cells may correlate with younger onset, and in PD cingulate neurons with younger death. Whole genome sequencing of 169 single cells from two MSA cases showed somatic CNVs in ~ 30%. Neurons had gains and losses, and other cells almost exclusively gains.We propose that somaticSNCACNVs contribute to the aetiology and pathogenesis of synucleinopathies, and that genome-wide somatic CNVs merit further studyc.proukakis@ucl.ac.uk