Investigation of somatic CNVs in brains of synucleinopathy cases using targeted SNCA analysis and single cell sequencing
-
Published:2019-12
Issue:1
Volume:7
Page:
-
ISSN:2051-5960
-
Container-title:Acta Neuropathologica Communications
-
language:en
-
Short-container-title:acta neuropathol commun
Author:
Perez-Rodriguez Diego, Kalyva Maria, Leija-Salazar Melissa, Lashley Tammaryn, Tarabichi Maxime, Chelban Viorica, Gentleman Steve, Schottlaender Lucia, Franklin Hannah, Vasmatzis George, Houlden Henry, Schapira Anthony H. V., Warner Thomas T., Holton Janice L., Jaunmuktane Zane, Proukakis ChristosORCID
Abstract
AbstractSynucleinopathies 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.
Funder
Michael J. Fox Foundation for Parkinson's Research
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Clinical Neurology,Pathology and Forensic Medicine
Reference123 articles.
1. Ahmed Z, Asi YT, Lees AJ, Revesz T, Holton JL (2013) Identification and quantification of oligodendrocyte precursor cells in multiple system atrophy, progressive supranuclear palsy and Parkinson’s disease. Brain Pathol 23:263–273. https://doi.org/10.1111/j.1750-3639.2012.00637.x 2. Alegre-Abarrategui J, Brimblecombe KR, Roberts RF, Velentza-Almpani E, Tilley BS, Bengoa-Vergniory N, Proukakis C (2019) Selective vulnerability in α-synucleinopathies. Acta Neuropathol. https://doi.org/10.1007/s00401-019-02010-2 3. Angermueller C, Clark SJ, Lee HJ, Macaulay IC, Teng MJ, Hu TX, Krueger F, Smallwood SA, Ponting CP, Voet T, Kelsey G, Stegle O, Reik W (2016) Parallel single-cell sequencing links transcriptional and epigenetic heterogeneity. Nat Methods 13:229–232. https://doi.org/10.1038/nmeth.3728 4. Audano PA, Sulovari A, Graves-Lindsay TA, Cantsilieris S, Sorensen M, Welch AE, Dougherty ML, Nelson BJ, Shah A, Dutcher SK, Warren WC, Magrini V, McGrath SD, Li YI, Wilson RK, Eichler EE (2019) Characterizing the major structural variant alleles of the human genome. Cell 176:663–675.e19. https://doi.org/10.1016/j.cell.2018.12.019 5. Bae T, Tomasini L, Mariani J, Zhou B, Roychowdhury T, Franjic D, Pletikos M, Pattni R, Chen B-J, Venturini E, Riley-Gillis B, Sestan N, Urban AE, Abyzov A, Vaccarino FM (2017) Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis. Science 555(80):eaan8690. https://doi.org/10.1126/science.aan8690
Cited by
34 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|