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We previously reported somatic copy number variants (CNVs), specifically gains of\n                    <jats:italic>SNCA<\/jats:italic>\n                    (encoding \u03b1-synuclein) in MSA brains. Here, we expand on this work by combining fluorescent in situ hybridisation for\n                    <jats:italic>SNCA<\/jats:italic>\n                    on nuclei with \u03b1-synuclein and SOX10 immunofluorescence, to assess oligodendrocyte-specific\n                    <jats:italic>SNCA<\/jats:italic>\n                    gains and losses, and their relationship with inclusions across differentially affected regions in two MSA subtypes: striatonigral degeneration (SND) and olivopontocerebellar atrophy (OPCA). Analysis of 13 SND, 12 OPCA and 15 control brains demonstrated significantly higher somatic\n                    <jats:italic>SNCA<\/jats:italic>\n                    CNVs, both gains and losses, in MSA oligodendrocytes compared with controls (gains: 6.3% vs 2.0%; losses: 12.5% vs 7.4%,\n                    <jats:italic>p<\/jats:italic>\n                    &lt; 0.0001 for both). Oligodendrocyte\n                    <jats:italic>SNCA<\/jats:italic>\n                    gains were high in the preferentially affected regions (putamen in SND, cerebellum in OPCA), where they were associated with a twofold increased presence of \u03b1-synuclein inclusions in the same cell (\n                    <jats:italic>p<\/jats:italic>\n                    &lt; 0.0001). Higher gain burden correlated with earlier disease onset (rho = \u2212\u20090.45,\n                    <jats:italic>p<\/jats:italic>\n                    = 0.03). Oligodendrocyte\n                    <jats:italic>SNCA<\/jats:italic>\n                    losses, conversely, showed less regional predilection, limited association with inclusions and no correlation with onset age. As double-strand DNA breaks have been reported in Lewy body diseases, we used immunofluorescence for \u03b3H2AX in a subset of experiments. The proportion of \u03b3H2AX-positive cells was significantly higher in MSA than controls overall (4.9% vs 2.5%,\n                    <jats:italic>p<\/jats:italic>\n                    = 0.01), in oligodendrocytes (9.7% vs 2.5%,\n                    <jats:italic>p<\/jats:italic>\n                    = 0.024) and in other cells (3.2% vs 1.1%;\n                    <jats:italic>p<\/jats:italic>\n                    = 0.048). The proportion of \u03b3H2AX-positive cells was also higher in preferentially affected regions (6.3% vs 3.5%,\n                    <jats:italic>p<\/jats:italic>\n                    = 0.004) and in inclusion-bearing cells (22.2% vs 14.9%,\n                    <jats:italic>p<\/jats:italic>\n                    = 0.02). These findings define the oligodendrocyte-specific patterns of somatic\n                    <jats:italic>SNCA<\/jats:italic>\n                    CNVs in MSA, support a role for gains in MSA pathogenesis and demonstrate the presence of\n                    <jats:italic>SNCA<\/jats:italic>\n                    losses and DNA double-strand breaks which require further investigation.\n                  <\/jats:p>","DOI":"10.1007\/s00401-026-03077-4","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T13:42:07Z","timestamp":1788529327000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Oligodendroglial somatic SNCA copy number gains are associated with inclusions and disease onset in multiple system atrophy"],"prefix":"10.1007","volume":"152","author":[{"given":"Caoimhe","family":"Morley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ester","family":"Kalef-Ezra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Perez-Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zane","family":"Jaunmuktane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christos","family":"Proukakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"3077_CR1","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/S0896-6273(00)80886-7","volume":"25","author":"A Abeliovich","year":"2000","unstructured":"Abeliovich A, Schmitz Y, Fari\u00f1as I, Choi-Lundberg D, Ho WH, Castillo PE et al (2000) Mice lacking \u03b1-synuclein display functional deficits in the nigrostriatal dopamine system. 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