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Similar to Parkinson's disease (PD), MSA is an \u03b1\u2010synucleinopathy, and its pathological hallmark consists of glial cytoplasmic inclusions (GCIs) containing \u03b1\u2010synuclein (SNCA) in oligodendrocytes. We previously identified consistent changes in myelin\u2010associated oligodendrocyte basic protein (<jats:italic>MOBP<\/jats:italic>) and huntingtin interacting protein 1 (<jats:italic>HIP1<\/jats:italic>) DNA methylation status in MSA. We hypothesized that if differential DNA methylation at these loci is mechanistically relevant for MSA, it should have downstream consequences on gene regulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We investigated the relationship between <jats:italic>MOBP<\/jats:italic> and <jats:italic>HIP1<\/jats:italic> DNA methylation and mRNA levels in cerebellar white matter from MSA and healthy controls. Additionally, we analysed protein expression using western blotting, immunohistochemistry and proximity ligation assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found decreased <jats:italic>MOBP<\/jats:italic> mRNA levels significantly correlated with increased DNA methylation in MSA. For <jats:italic>HIP1<\/jats:italic>, we found a distinct relationship between DNA methylation and gene expression levels in MSA compared to healthy controls, suggesting this locus may be subjected to epigenetic remodelling in MSA. Although soluble protein levels for MOBP and HIP1 in cerebellar white matter were not significantly different between MSA cases and controls, we found striking differences between MSA and other neurodegenerative diseases, including PD and Huntington's disease. We also found that MOBP and HIP1 are mislocalized into the GCIs in MSA, where they appear to interact with SNCA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study supports a role for DNA methylation in downregulation of <jats:italic>MOBP<\/jats:italic> mRNA in MSA. Most importantly, the identification of MOBP and HIP1 as new constituents of GCIs emphasizes the relevance of these two loci to the pathogenesis of MSA.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nan.12688","type":"journal-article","created":{"date-parts":[[2020,12,25]],"date-time":"2020-12-25T03:15:23Z","timestamp":1608866123000},"page":"640-652","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["MOBP and HIP1 in multiple system atrophy: New \u03b1\u2010synuclein partners in glial cytoplasmic inclusions implicated in the disease pathogenesis"],"prefix":"10.1111","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9090-7690","authenticated-orcid":false,"given":"Concei\u00e7\u00e3o","family":"Bettencourt","sequence":"first","affiliation":[{"name":"Queen Square Brain Bank for Neurological Disorders UCL Queen Square Institute of Neurology  London UK"},{"name":"Department of Clinical and Movement Neurosciences 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