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The autophagy‐enhancing drug carbamazepine improves neuropathology and motor impairment in mouse models of Machado–Joseph disease

2021Journal article Restricted
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dc.contributor.authorVasconcelos‐Ferreira, Ana
dc.contributor.authorCarmo‐Silva, Sara
dc.contributor.authorCodêsso, José Miguel
dc.contributor.authorSilva, Patrick
dc.contributor.authorMartinez, Alberto Rolim Muro
dc.contributor.authorFrança Jr, Marcondes Cavalcante
dc.contributor.authorNóbrega, Clévio
dc.contributor.authorPereira de Almeida, Luís
dc.date.accessioned2022-01-03T16:49:58Z
dc.date.available2022-01-03T16:49:58Z
dc.date.issued2021
dc.description.abstractAims Machado-Joseph disease (MJD), or spinocerebellar ataxia type 3 (SCA3), is the most common autosomal dominantly-inherited ataxia worldwide and is characterised by the accumulation of mutant ataxin-3 (mutATXN3) in different brain regions, leading to neurodegeneration. 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. Methods The autophagy-enhancing activity of CBZ and its effects on clearance of mutATXN3 were evaluated using in vitro and in vivo 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-associated motor deficits and neuropathology. A retrospective study was conducted to evaluate the CBZ effect in MJD patients. Results 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-regulated autophagy through activation of AMPK, which was dependent on the myo-inositol 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. Conclusions Our data support the autophagy-enhancing activity of CBZ in the brain and suggest this pharmacological approach as a promising therapy for MJD and other polyglutamine disorders.pt_PT
dc.description.sponsorshipFundação para Ciência e Tecnologia; Richard Chin and Lily Lock Machado-Joseph Disease Research Fund; American Portuguese Biomedical Research Fund (APBRF); National Ataxia Foundation (USA); European Union H2020 program, GA No.643417; EU Joint Program - Neurodegenerative Disease Research (JPND); Competitiveness Factors Operational Program (COMPETE 2020); ERDF through the Regional Operational Program Center 2020pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1111/nan.12763pt_PT
dc.identifier.issn0305-1846
dc.identifier.urihttp://hdl.handle.net/10400.1/17416
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherWileypt_PT
dc.relationERA-NET for establishing synergies between the Joint Programming on Neurodegenerative Diseases Research and Horizon 2020
dc.subjectAtaxin-3pt_PT
dc.subjectAutophagypt_PT
dc.subjectCarbamazepinept_PT
dc.subjectMachado-Joseph diseasept_PT
dc.subjectNeuroprotectionpt_PT
dc.titleThe autophagy‐enhancing drug carbamazepine improves neuropathology and motor impairment in mouse models of Machado–Joseph diseasept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleERA-NET for establishing synergies between the Joint Programming on Neurodegenerative Diseases Research and Horizon 2020
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/643417/EU
oaire.citation.titleNeuropathology and Applied Neurobiologypt_PT
oaire.fundingStreamH2020
person.familyNameAntunes Codêsso
person.familyNameNóbrega
person.givenNameJosé Miguel
person.givenNameClévio
person.identifier.ciencia-id9D1C-5F50-904E
person.identifier.ciencia-idC510-7F41-BAF8
person.identifier.orcid0000-0002-8312-5292
person.identifier.ridM-6047-2013
person.identifier.scopus-author-id24473454000
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameEuropean Commission
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication180cd953-3366-4970-8d65-4ba5fc4ceab2
relation.isAuthorOfPublication725ea6f8-1363-4cee-9cf2-5ac7303b3ba9
relation.isAuthorOfPublication.latestForDiscovery725ea6f8-1363-4cee-9cf2-5ac7303b3ba9
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