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Sacsin is a multidomain protein that plays key roles in chaperone regulation, protein quality control, and neurofilament dynamics. Sacsin deficiency leads to disruption of intermediate filament and mitochondrial networks. S100B, a multifunctional brain-enriched protein, exhibits protective neuroprotective functions that include chaperone activity and interactions with filament proteins and mitochondria. In this study, we used an established astroglial C6 cell model of ARSACS to investigate the potential compensatory effects of S100B on sacsin loss with respect to neurofilament integrity and mitochondrial morphological and functional hallmarks. Our results demonstrate that sacsin deletion induces S100B upregulation at both mRNA and protein levels, with the S100B protein colocalizing with perinuclear nestin aggregates and filamentous mitochondria networks. Genetic silencing and pharmacological inhibition of S100B exacerbate filament protein aggregation and mitochondrial defects, while supplementation with exogenous recombinant S100B improves ARSACS hallmarks, including decreased nestin aggregates. These findings provide evidence for functional compensation of sacsin loss by S100B in glial cells, and suggests a potential role for glial cells in ARSACS.<\/jats:p>","DOI":"10.1007\/s12035-025-05057-3","type":"journal-article","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T16:49:16Z","timestamp":1747673356000},"page":"12296-12306","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["S100B Mitigates Cytoskeletal and Mitochondrial Alterations in a Glial Cell Model of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay"],"prefix":"10.1007","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8273-6502","authenticated-orcid":false,"given":"Ana Sofia","family":"Boasinha","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5096-5631","authenticated-orcid":false,"given":"Fernanda","family":"Murtinheira","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2036-797X","authenticated-orcid":false,"given":"Susana","family":"Sol\u00e1","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4662-6933","authenticated-orcid":false,"given":"Cl\u00e1udio M.","family":"Gomes","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9596-9353","authenticated-orcid":false,"given":"Federico","family":"Herrera","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,5,19]]},"reference":[{"issue":"1","key":"5057_CR1","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1007\/s12311-024-01777-9","volume":"24","author":"IH Salem","year":"2025","unstructured":"Salem IH, Blais M, Zuluaga-S\u00e1nchez VM et al (2025) ARSACS: clinical features, pathophysiology and iPS-derived models. 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