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ULK overexpression mitigates motor deficits and neuropathology in mouse models of Machado-Joseph disease

2022-01Journal article Restricted
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dc.contributor.authorVasconcelos-Ferreira, Ana
dc.contributor.authorMartins, Inês Morgado
dc.contributor.authorLobo, Diana
dc.contributor.authorPereira, Dina
dc.contributor.authorLopes, Miguel M.
dc.contributor.authorFaro, Rosário
dc.contributor.authorLopes, Sara M.
dc.contributor.authorVerbeek, Dineke
dc.contributor.authorSchmidt, Thorsten
dc.contributor.authorNóbrega, Clévio
dc.contributor.authorPereira de Almeida, Luís
dc.date.accessioned2023-03-13T11:11:56Z
dc.date.available2023-03-13T11:11:56Z
dc.date.issued2022-01
dc.description.abstractMachado-Joseph disease (MJD) is a fatal neurodegenerative disorder clinically characterized by prominent ataxia. It is caused by an expansion of a CAG trinucleotide in ATXN3, translating into an expanded polyglutamine (polyQ) tract in the ATXN3 protein, that becomes prone to misfolding and aggregation. The pathogenesis of the disease has been associated with the dysfunction of several cellular mechanisms, including autophagy and transcription regulation. In this study, we investigated the transcriptional modifications of the autophagy pathway in models of MJD and assessed whether modulating the levels of the affected autophagy-associated transcripts (AATs) would alleviate MJD-associated pathology. Our results show that autophagy is impaired at the transcriptional level in phagy activating kinase 1 and 2 (ULK1 and ULK2), two homologs involved in autophagy induction. Reinstating ULK1/2 levels by adeno-associated virus (AAV)-mediated gene transfer significantly improved motor performance while preventing in vitro studies showed that the observed positive effects may be mainly attributed to ULK1 activity. This study provides strong evidence of the beneficial effect of overexpression of ders.pt_PT
dc.description.sponsorshipnational funds through FCT (Foundation for Science and Technology) -Brain Health2020 projects CENTRO-01-0145-FEDER-000008, UID/NEU/04539/2020, CENTRO-01-0145-FEDER-022095, PTDC/NEU-NMC/0084/2014|POCI-01-0145-FEDER-016719, POCI-01-0145-FEDER-029716, POCI-01-0145-FEDER-016807, POCI-01-0145-FEDER-016390, POCI-01-0145-FEDER-032309,pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1016/j.ymthe.2021.07.012pt_PT
dc.identifier.eissn1525-0024
dc.identifier.urihttp://hdl.handle.net/10400.1/19229
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherCell Presspt_PT
dc.relationERA-NET for establishing synergies between the Joint Programming on Neurodegenerative Diseases Research and Horizon 2020
dc.relationINVESTIGATING TRANSCRIPTIONAL MODIFICATIONS OF THE AUTOPHAGY PATHWAY IN MACHADO-JOSEPH DISEASE
dc.subjectPolyglutamine-Expanded Ataxin-3pt_PT
dc.subjectMutant Huntingtpt_PT
dc.subjectIntranuclear Inclusionspt_PT
dc.subjectNuclear-Localizationpt_PT
dc.subjectCerebellar-Aaxiagene-Productcell-Linespt_PT
dc.subjectRat Modelin-Vitropt_PT
dc.subjectAutophagypt_PT
dc.titleULK overexpression mitigates motor deficits and neuropathology 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.awardTitleINVESTIGATING TRANSCRIPTIONAL MODIFICATIONS OF THE AUTOPHAGY PATHWAY IN MACHADO-JOSEPH DISEASE
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/643417/EU
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/FARH/SFRH%2FBD%2F87804%2F2012/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/E-Rare4%2F0003%2F2012/PT
oaire.citation.endPage387pt_PT
oaire.citation.issue1pt_PT
oaire.citation.startPage370pt_PT
oaire.citation.titleMolecular Therapypt_PT
oaire.citation.volume30pt_PT
oaire.fundingStreamH2020
oaire.fundingStreamFARH
oaire.fundingStream3599-PPCDT
person.familyNameNóbrega
person.givenNameClévio
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.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameEuropean Commission
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication725ea6f8-1363-4cee-9cf2-5ac7303b3ba9
relation.isAuthorOfPublication.latestForDiscovery725ea6f8-1363-4cee-9cf2-5ac7303b3ba9
relation.isProjectOfPublicationf83d8467-3845-465e-97d6-91c6ed1f4267
relation.isProjectOfPublication47a4b409-dcd1-42bc-87e2-be964adcd651
relation.isProjectOfPublicationa29d76e0-60e6-4110-868c-ad0589af6f0d
relation.isProjectOfPublication.latestForDiscoveryf83d8467-3845-465e-97d6-91c6ed1f4267

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