Investigation of somatic CNVs in brains of synucleinopathy cases using targeted SNCA analysis and single cell sequencing
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 g...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-12-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-019-0873-5 |
| _version_ | 1818565165626425344 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Diego Perez-Rodriguez |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T01:37:44Z |
| format | Article |
| id | doaj.art-7ef14b0631654f92929d5d083479b9c2 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-14T01:37:44Z |
| publishDate | 2019-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-7ef14b0631654f92929d5d083479b9c22022-12-21T23:21:50ZengBMCActa Neuropathologica Communications2051-59602019-12-017112210.1186/s40478-019-0873-5Investigation of somatic CNVs in brains of synucleinopathy cases using targeted SNCA analysis and single cell sequencingDiego Perez-Rodriguez0Maria Kalyva1Melissa Leija-Salazar2Tammaryn Lashley3Maxime Tarabichi4Viorica Chelban5Steve Gentleman6Lucia Schottlaender7Hannah Franklin8George Vasmatzis9Henry Houlden10Anthony H. V. Schapira11Thomas T. Warner12Janice L. Holton13Zane Jaunmuktane14Christos Proukakis15Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of NeurologyDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of NeurologyDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of NeurologyQueen Square Brain Bank for Neurological disorders, UCL Queen Square Institute of NeurologyThe Francis Crick InstituteDepartment of Neuromuscular Diseases, UCL Queen Square Institute of NeurologyDepartment of Medicine, Imperial College LondonDepartment of Neuromuscular Diseases, UCL Queen Square Institute of NeurologyDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of NeurologyCenter for Individualized Medicine, Department of Molecular Medicine, Mayo ClinicDepartment of Neuromuscular Diseases, UCL Queen Square Institute of NeurologyDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of NeurologyDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of NeurologyDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of NeurologyDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of NeurologyDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of NeurologyAbstract 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.https://doi.org/10.1186/s40478-019-0873-5Multiple system atrophyParkinson’s diseaseAlpha-synucleinSNCASomatic mutationSingle cell sequencing |
| spellingShingle | 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 Investigation of somatic CNVs in brains of synucleinopathy cases using targeted SNCA analysis and single cell sequencing Acta Neuropathologica Communications Multiple system atrophy Parkinson’s disease Alpha-synuclein SNCA Somatic mutation Single cell sequencing |
| title | Investigation of somatic CNVs in brains of synucleinopathy cases using targeted SNCA analysis and single cell sequencing |
| title_full | Investigation of somatic CNVs in brains of synucleinopathy cases using targeted SNCA analysis and single cell sequencing |
| title_fullStr | Investigation of somatic CNVs in brains of synucleinopathy cases using targeted SNCA analysis and single cell sequencing |
| title_full_unstemmed | Investigation of somatic CNVs in brains of synucleinopathy cases using targeted SNCA analysis and single cell sequencing |
| title_short | Investigation of somatic CNVs in brains of synucleinopathy cases using targeted SNCA analysis and single cell sequencing |
| title_sort | investigation of somatic cnvs in brains of synucleinopathy cases using targeted snca analysis and single cell sequencing |
| topic | Multiple system atrophy Parkinson’s disease Alpha-synuclein SNCA Somatic mutation Single cell sequencing |
| url | https://doi.org/10.1186/s40478-019-0873-5 |
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