Abstract
Synucleinopathies are mostly sporadic neurodegenerative disorders of partly unexplained aetiology, and include Parkinson’s disease (PD) and multiple system atrophy (MSA). We have further investigated our recent finding of somatic SNCA (α-synuclein) copy number variants (CNVs, specifically gains) in synucleinopathies, using Fluorescent in-situ Hybridisation for SNCA, and single-cell whole genome sequencing for the first time in a synucleinopathy. In the cingulate cortex, mosaicism levels for SNCA gains were 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 noted SNCA gains in > 3% of dopaminergic (DA) neurons (identified by neuromelanin) and neuromelanin-negative cells, including olig2-positive oligodendroglia. Cells with CNVs were more likely to have α-synuclein inclusions, in a pattern corresponding to cell categories mostly relevant to the disease: DA neurons in Lewy-body cases, and other cells in the striatonigral degeneration-dominant MSA variant (MSA-SND). Higher mosaicism levels in SN neuromelanin-negative cells may correlate with younger onset in typical MSA-SND, and in cingulate neurons with younger death in PD. Larger sample sizes will, however, be required to confirm these putative findings. We obtained genome-wide somatic CNV profiles from 169 cells from the substantia nigra of two MSA cases, and pons and putamen of one. These showed somatic CNVs in ~ 30% of cells, with clonality and origins in segmental duplications for some. CNVs had distinct profiles based on cell type, with neurons having a mix of gains and losses, and other cells having almost exclusively gains, although control data sets will be required to determine possible disease relevance. We propose that somatic SNCA CNVs may contribute to the aetiology and pathogenesis of synucleinopathies, and that genome-wide somatic CNVs in MSA brain merit further study.
Highlights
Synucleinopathies are mostly sporadic neurodegenerative diseases characterised by aggregation of the αsynuclein protein, with a wide range of pathological and clinical features, and differential selective vulnerability of cell types and brain regions [2]
We previously reported the results of Fluorescent in situ Hybridisation (FISH) for SNCA in the substantia nigra (SN), where we found SNCA gains, more common in DA neurons in Parkinson’s disease (PD) than controls, the highest levels of DA neuron mosaicism were in two multiple system atrophy (MSA) cases [79]
SNCA gains in the cingulate cortex are more frequent in synucleinopathies than controls In our previous work, we analysed mostly the SN, and found higher mosaicism for SNCA copy number variations (CNVs) in NM+ cells in PD than controls
Summary
Synucleinopathies are mostly sporadic neurodegenerative diseases characterised by aggregation of the αsynuclein protein, with a wide range of pathological and clinical features, and differential selective vulnerability of cell types and brain regions [2]. They include Parkinson’s disease (PD), the closely related dementia with. Lewy Bodies (DLB), and multiple system atrophy (MSA). MSA can broadly be classified pathologically into the predominant types of striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), and mixed pathology, with approximately equal frequencies [75]. The clinical phenotype is determined by the pathology distribution, with SND resulting in a parkinsonian phenotype (MSA-P), and OPCA in a cerebellar [88]
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