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Autophagy in Spinocerebellar ataxia type 2, a dysregulated pathway, and a target for therapy

2021-11Journal article Open access
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dc.contributor.authorMarcelo, Adriana
dc.contributor.authorAfonso, Inês T.
dc.contributor.authorAfonso-Reis, Ricardo
dc.contributor.authorBrito, David V. C.
dc.contributor.authorCosta, Rafael G.
dc.contributor.authorRosa, Ana
dc.contributor.authorAlves-Cruzeiro, João
dc.contributor.authorFerreira, Benedita
dc.contributor.authorHenriques, Carina
dc.contributor.authorNobre, Rui J.
dc.contributor.authorMatos, Carlos A
dc.contributor.authorde Almeida, Luís Pereira
dc.contributor.authorNóbrega, Clévio
dc.date.accessioned2021-12-10T16:45:41Z
dc.date.available2021-12-10T16:45:41Z
dc.date.issued2021-11
dc.description.abstractSpinocerebellar ataxia type 2 (SCA2) is an incurable and genetic neurodegenerative disorder. The disease is characterized by progressive degeneration of several brain regions, resulting in severe motor and non-motor clinical manifestations. The mutation causing SCA2 disease is an abnormal expansion of CAG trinucleotide repeats in the ATXN2 gene, leading to a toxic expanded polyglutamine segment in the translated ataxin-2 protein. While the genetic cause is well established, the exact mechanisms behind neuronal death induced by mutant ataxin-2 are not yet completely understood. Thus, the goal of this study is to investigate the role of autophagy in SCA2 pathogenesis and investigate its suitability as a target for therapeutic intervention. For that, we developed and characterized a new striatal lentiviral mouse model that resembled several europathological hallmarks observed in SCA2 disease, including formation of aggregates, neuronal marker loss, cell death and neuroinflammation. In this new model, we analyzed autophagic markers, which were also analyzed in a SCA2 cellular model and in human post-mortem brain samples. Our results showed altered levels of SQSTM1 and LC3B in cells and tissues expressing mutant ataxin-2. Moreover, an abnormal accumulation of these markers was detected in SCA2 patients’ striatum and cerebellum. Importantly, the molecular activation of autophagy, using the compound cordycepin, mitigated the phenotypic alterations observed in disease models. Overall, our study suggests an important role for autophagy in the context of SCA2 pathology, proposing that targeting this pathway could be a potential target to treat SCA2 patients.pt_PT
dc.description.sponsorshipPPBI-POCI-01-0145-FEDER-022122; ALG-01-0145-FEDER-29480
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1038/s41419-021-04404-1pt_PT
dc.identifier.issn2041-4889
dc.identifier.urihttp://hdl.handle.net/10400.1/17372
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringernaturept_PT
dc.relation22424pt_PT
dc.relationStress granules in Polyglutamine diseases: new targets for therapeutic intervention
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectInclusões intranucleares neuronaispt_PT
dc.subjectMutante Ataxin-3pt_PT
dc.subjectExpansão repetidapt_PT
dc.subjectModelo RATpt_PT
dc.subjectSCA 2pt_PT
dc.subjectDoençapt_PT
dc.subjectExpessãopt_PT
dc.subjectRatopt_PT
dc.subjectProtaínapt_PT
dc.subjectPatologiapt_PT
dc.titleAutophagy in Spinocerebellar ataxia type 2, a dysregulated pathway, and a target for therapypt_PT
dc.title.alternativeAutofagia em Spinocerebellar ataxia tipo 2, uma via disregulada, e um alvo para a terapiapt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleStress granules in Polyglutamine diseases: new targets for therapeutic intervention
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F133192%2F2017/PT
oaire.citation.issue12pt_PT
oaire.citation.titleCell Death & Diseasept_PT
oaire.citation.volume12pt_PT
person.familyNameMarcelo
person.familyNameAlbuquerque Andrade de Matos
person.familyNameNóbrega
person.givenNameAdriana
person.givenNameCarlos Adriano
person.givenNameClévio
person.identifier.ciencia-id7613-00C2-1621
person.identifier.ciencia-idDC14-C299-222A
person.identifier.ciencia-idC510-7F41-BAF8
person.identifier.orcid0000-0002-7327-0170
person.identifier.orcid0000-0002-9019-7569
person.identifier.orcid0000-0002-8312-5292
person.identifier.ridM-6047-2013
person.identifier.scopus-author-id24473454000
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication3bed3cc3-e36a-445b-8d7d-4d4615ff4c4c
relation.isAuthorOfPublication31434f2c-76dd-49e4-a78e-324ab36b81bb
relation.isAuthorOfPublication725ea6f8-1363-4cee-9cf2-5ac7303b3ba9
relation.isAuthorOfPublication.latestForDiscovery725ea6f8-1363-4cee-9cf2-5ac7303b3ba9
relation.isProjectOfPublication632bda32-a476-47bf-a394-6344df28e62f
relation.isProjectOfPublication.latestForDiscovery632bda32-a476-47bf-a394-6344df28e62f

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