Investigation of somatic CNVs in brains of synucleinopathy cases using targeted SNCA analysis and single cell sequencing

Diego Perez-Rodriguez, Maria Kalyva, Melissa Leija-Salazar, Tammaryn Lashley, Maxime Tarabichi, Viorica Chelban, Steve Gentleman, Lucia Schottlaender, Hannah Franklin, George Vasmatzis, Henry Houlden, Anthony H.V. Schapira, Thomas T. Warner, Janice L. Holton, Zane Jaunmuktane, Christos Proukakis

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish (US)
Article number219
JournalActa Neuropathologica Communications
Issue number1
StatePublished - Dec 23 2019


  • Alpha-synuclein
  • Mosaicism
  • Multiple system atrophy
  • Parkinson's disease
  • SNCA
  • Single cell sequencing
  • Somatic mutation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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