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Mutation of\n                    <jats:italic>ATXN3<\/jats:italic>\n                    causes formation of ataxin\u20103 protein aggregates, neurodegeneration, and motor deficits. Here we investigated the therapeutic potential and mechanistic activity of sodium butyrate (SB), the sodium salt of butyric acid, a metabolite naturally produced by gut microbiota, on cultured SH\u2010SY5Y cells and transgenic zebrafish expressing human ataxin\u20103 containing 84 glutamine (Q) residues to model SCA3. SCA3 SH\u2010SY5Y cells were found to contain high molecular weight ataxin\u20103 species and detergent\u2010insoluble protein aggregates. Treatment with SB increased the activity of the autophagy protein quality control pathway in the SCA3 cells, decreased the presence of ataxin\u20103 aggregates and presence of high molecular weight ataxin\u20103 in an autophagy\u2010dependent manner. Treatment with SB was also beneficial in\u00a0vivo, improving swimming performance, increasing activity of the autophagy pathway, and decreasing the presence of insoluble ataxin\u20103 protein species in the transgenic SCA3 zebrafish. Co\u2010treating the SCA3 zebrafish with SB and chloroquine, an autophagy inhibitor, prevented the beneficial effects of SB on zebrafish swimming, indicating that the improved swimming performance was autophagy\u2010dependent. To understand the mechanism by which SB induces autophagy we performed proteomic analysis of protein lysates from the SB\u2010treated and untreated SCA3 SH\u2010SY5Y cells. We found that SB treatment had increased activity of Protein Kinase A and AMPK signaling, with immunoblot analysis confirming that SB treatment had increased levels of AMPK protein and its substrates. Together our findings indicate that treatment with SB can increase activity of the autophagy pathway process and that this has beneficial effects in\u00a0vitro and in\u00a0vivo. While our results suggested that this activity may involve activity of a PKA\/AMPK\u2010dependent process, this requires further confirmation. We propose that treatment with sodium butyrate warrants further investigation as a potential treatment for neurodegenerative diseases underpinned by mechanisms relating to protein aggregation including SCA3.\n                  <\/jats:p>","DOI":"10.1096\/fj.202300963rr","type":"journal-article","created":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T07:23:40Z","timestamp":1705994620000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Treatment with sodium butyrate induces autophagy resulting in therapeutic benefits for spinocerebellar ataxia\u00a0type 3"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8400-4994","authenticated-orcid":false,"given":"Maxinne","family":"Watchon","sequence":"first","affiliation":[{"name":"Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences Macquarie University  Sydney New South Wales 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