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Currently, there are no available treatments able to block disease progression. In this study, we investigated whether carbamazepine (CBZ) would activate autophagy and mitigate MJD pathology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The autophagy\u2010enhancing activity of CBZ and its effects on clearance of mutATXN3 were evaluated using <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> models of MJD. To investigate the optimal treatment regimen, a daily or intermittent CBZ administration was applied to MJD transgenic mice expressing a truncated human ATXN3 with 69 glutamine repeats. Motor behaviour tests and immunohistology was performed to access the alleviation of MJD\u2010associated motor deficits and neuropathology. A retrospective study was conducted to evaluate the CBZ effect in MJD patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that CBZ promoted the activation of autophagy and the degradation of mutATXN3 in MJD models upon short or intermittent, but not daily prolonged, treatment regimens. CBZ up\u2010regulated autophagy through activation of AMPK, which was dependent on the myo\u2010inositol levels. In addition, intermittent CBZ treatment improved motor performance, as well as prevented neuropathology in MJD transgenic mice. However, in patients, no evident differences in SARA scale were found, which was not unexpected given the small number of patients included in the study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our data support the autophagy\u2010enhancing activity of CBZ in the brain and suggest this pharmacological approach as a promising therapy for MJD and other polyglutamine disorders.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nan.12763","type":"journal-article","created":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T12:34:48Z","timestamp":1629894888000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["The autophagy\u2010enhancing drug carbamazepine improves neuropathology and motor impairment in mouse models of Machado\u2013Joseph disease"],"prefix":"10.1111","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8968-0641","authenticated-orcid":false,"given":"Ana","family":"Vasconcelos\u2010Ferreira","sequence":"first","affiliation":[{"name":"CNC\u2010Center for Neuroscience and Cell Biology University of Coimbra  Coimbra Portugal"},{"name":"CIBB\u2010Center for Innovative Biomedicine and Biotechnology University of Coimbra  Coimbra Portugal"},{"name":"Faculty of Pharmacy University of Coimbra  Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6124-0428","authenticated-orcid":false,"given":"Sara","family":"Carmo\u2010Silva","sequence":"additional","affiliation":[{"name":"CNC\u2010Center for Neuroscience and Cell Biology University of Coimbra  Coimbra Portugal"},{"name":"CIBB\u2010Center for Innovative Biomedicine and Biotechnology University of Coimbra  Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Miguel","family":"Cod\u00easso","sequence":"additional","affiliation":[{"name":"CNC\u2010Center for Neuroscience and Cell Biology University of Coimbra  Coimbra Portugal"},{"name":"CIBB\u2010Center for Innovative Biomedicine and Biotechnology University of Coimbra  Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5436-8949","authenticated-orcid":false,"given":"Patrick","family":"Silva","sequence":"additional","affiliation":[{"name":"CNC\u2010Center for Neuroscience and Cell Biology University of Coimbra  Coimbra Portugal"},{"name":"CIBB\u2010Center for Innovative Biomedicine and Biotechnology University of Coimbra  Coimbra Portugal"},{"name":"Faculty of Pharmacy University of Coimbra  Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto Rolim 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