Somatic copy number gains of α-synuclein (SNCA) in Parkinson's disease and multiple system atrophy brains

• Published in: Brain (London, England : 1878) England : 1878), 2018-08, Vol.141 (8), p.2419-2431
• Main Authors: Mokretar, Katya, Pease, Daniel, Taanman, Jan-Willem, Soenmez, Aynur, Ejaz, Ayesha, Lashley, Tammaryn, Ling, Helen, Gentleman, Steve, Houlden, Henry, Holton, Janice L, Schapira, Anthony H V, Nacheva, Elizabeth, Proukakis, Christos
• Format: Article
• Language: English
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awy157

The alpha-synuclein protein is important in the pathogenesis of synucleinopathies, but mutations in the SNCA gene are very rarely found. Mokretar et al. demonstrate somatic copy number gains of SNCA in a small proportion of substantia nigra dopaminergic neurons, commoner in Parkinson's disease, and possibly multiple system atrophy, than controls. Abstract The α-synuclein protein, encoded by SNCA, has a key role in the pathogenesis of Parkinson's disease and other synucleinopathies. Although usually sporadic, Parkinson's disease can result from inherited copy number variants in SNCA and other genes. We have hypothesized a role of somatic SNCA mutations, leading to mosaicism, in sporadic synucleinopathies. The evidence for mosaicism in healthy and diseased brain is increasing rapidly, with somatic copy number gains of APP reported in Alzheimer's brain. Here we demonstrate somatic SNCA copy number gains in synucleinopathies (Parkinson's disease and multiple system atrophy), focusing on substantia nigra. We selected sporadic cases with relatively young onset or short disease duration, and first excluded high level copy number variant mosaicism by DNA analysis using digital PCR for SNCA, and/or customized array comparative genomic hybridization. To detect low level SNCA copy number variant mosaicism, we used fluorescent in situ hybridization with oligonucleotide custom-designed probes for SNCA, validated on brain and fibroblasts with known copy number variants. We determined SNCA copy number in nigral dopaminergic neurons and other cells in frozen nigra sections from 40 cases with Parkinson's disease and five with multiple system atrophy, and 25 controls, in a blinded fashion. Parkinson's disease cases were significantly more likely than controls to have any SNCA gains in dopaminergic neurons (P = 0.0036), and overall (P = 0.0052). The average proportion of dopaminergic neurons with gains in each nigra was significantly higher in Parkinson's disease than controls (0.78% versus 0.45%; P = 0.017). There was a negative correlation between the proportion of dopaminergic neurons with gains and onset age in Parkinson's disease (P = 0.013), but not with disease duration, or age of death in cases or controls. Cases with tremor at onset were less likely to have gains (P = 0.035). All multiple system atrophy cases had gains, and the highest levels in dopaminergic neurons were in two of these cases (2.76%, 2.48%). We performed selective validation with different probes af