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Extensive demyelination occurs particularly in the olivopontocerebellar and striatonigral pathways, but its precise mechanism remains elusive. Glial connexins (Cxs), which form gap junction channels between astrocytes and oligodendrocytes, play critical roles in myelin maintenance, and have not been studied in MSA. Therefore, we immunohistochemically investigated glial Cx changes in the cerebellar afferent fibers in 15 autopsied patients with MSA. We classified demyelinating lesions into three stages based on Kl\u00fcver\u2013Barrera staining: early (Stage I), intermediate (Stage II), and late (Stage III) stages showing subtle, moderate, and severe myelin reduction, respectively. Myelin\u2010associated glycoprotein, but not myelin oligodendrocyte glycoprotein, was preferentially decreased in Stage I, suggesting distal oligodendrogliopathy type demyelination. Accumulation of phosphorylated \u03b1\u2010synuclein in oligodendrocytes was frequently seen in Stage I but less frequently observed in Stages II and III. Tubulin polymerization\u2010promoting protein (TPPP\/p25\u03b1)\u2010positive oligodendrocytes were preserved in Stage I but successively decreased in Stages II and III. Even at Stage I, Cx32 was nearly absent from myelin, despite the relative preservation of other nodal proteins, such as neurofascin, claudin\u201011\/oligodendrocyte\u2010specific protein, and contactin\u2010associated protein 1, which successively decreased in the later stages. Cx32 was re\u2010distributed in the oligodendrocyte cytoplasm and co\u2010localized with GCIs. Cx47 gradually decreased at the oligodendrocyte surface in a stage\u2010dependent manner but was not co\u2010localized with GCIs. Astrocytic Cx43 was down\u2010regulated in Stage I but up\u2010regulated in Stages II and III, reflecting astrogliosis. Cx43\/Cx47 gap junctions significantly decreased from Stage I to III. Activated microglia\/macrophages and T cells infiltrated in Stage I rather than Stages II and III. Therefore, early and extensive alterations of glial Cxs, particularly Cx32 loss, occur in MSA and may accelerate distal oligodendrogliopathy type demyelination and nodal\/paranodal dysfunction through disruption of inter\u2010glial communication.<\/jats:p>","DOI":"10.1111\/bpa.13131","type":"journal-article","created":{"date-parts":[[2022,11,12]],"date-time":"2022-11-12T01:30:26Z","timestamp":1668216626000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Early and extensive alterations of glial connexins, distal oligodendrogliopathy type demyelination, and nodal\/paranodal pathology are characteristic of multiple system atrophy"],"prefix":"10.1111","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3896-2438","authenticated-orcid":false,"given":"Yuji","family":"Nishimura","sequence":"first","affiliation":[{"name":"Department of Neurology, Neurological Institute, Graduate School of Medical Sciences 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