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Cordycepin activates autophagy through AMPK phosphorylation to reduce abnormalities in Machado-Joseph disease models

2019-01Journal article Open Access
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dc.contributor.authorMarcelo, Adriana
dc.contributor.authorBrito, Filipa
dc.contributor.authorCarmo-Silva, Sara
dc.contributor.authorMatos, Carlos A.
dc.contributor.authorAlves-Cruzeiro, Joao
dc.contributor.authorVasconcelos-Ferreira, Ana
dc.contributor.authorKoppenol, Rebekah
dc.contributor.authorMendonca, Liliana
dc.contributor.authorde Almeida, Luis Pereira
dc.contributor.authorNóbrega, Clévio
dc.date.accessioned2020-07-24T10:53:21Z
dc.date.available2020-07-24T10:53:21Z
dc.date.issued2019-01
dc.description.abstractMachado-Joseph disease (MJD) is a neurodegenerative disorder caused by an abnormal expansion of citosine-adenine-guanine trinucleotide repeats in the disease-causing gene. This mutation leads to an abnormal polyglutamine tract in the protein ataxin-3 (Atx3), resulting in formation of mutant Atx3 aggregates. Despite several attempts to develop a therapeutic option for MJD, currently there are no available therapies capable of delaying or stopping disease progression. Recently, our group reported that reducing the expression levels of mutant Atx3 lead to a mitigation of several MJD-related behavior and neuropathological abnormalities. Aiming a more rapid translation to the human clinics, in this study we investigate a pharmacological inhibitor of translation-cordycepin-in several preclinical models. We found that cordycepin treatment significantly reduced (i) the levels of mutant Atx3, (ii) the neuropathological abnormalities in a lentiviral mouse model, (iii) the motor and neuropathological deficits in a transgenic mouse model and (iv) the number of ubiquitin aggregates in a human neural model. We hypothesize that the effect of cordycepin is mediated by the increase of phosphorylated adenosine monophosphate-activated protein kinase (AMPK) levels, which is accompanied by a reduction in the global translation levels and by a significant activation of the autophagy pathway. Overall, this study suggests that cordycepin might constitute an effective and safe therapeutic approach for MJD, and probably for the other polyglutamine diseases.
dc.description.sponsorshipEuropean Union through the European social fund, funds Fundo Europeu de Desenvolvimento Regional through the Competitive Factors Operational Program-COMPETE, POPH and QREN
dc.description.sponsorshipFrench Muscular Dystrophy Association (AFM-Telethon) [18776]
dc.description.sponsorshipAtaxia UK
dc.description.sponsorshipFundacao para a Ciencia e TecnologiaPortuguese Foundation for Science and Technology [SFRH/BD/133192/2017]
dc.description.sponsorshipFCT - Fundacao para a Ciencia e a Tecnologia, I.P. [UID/BIM/04773/2013 CBMR]
dc.identifier.doi10.1093/hmg/ddy328
dc.identifier.issn0964-6906
dc.identifier.issn1460-2083
dc.identifier.urihttp://hdl.handle.net/10400.1/14482
dc.language.isoeng
dc.peerreviewedyes
dc.publisherOxford Univ Press
dc.relationDYNAMIC BRAIN FUNCTION: Towards the Understanding and Treatment of Brain Disorders
dc.subjectMutant Ataxin-3
dc.subjectRat Model
dc.subjectProtein
dc.subjectNeuropathology
dc.subjectHepatotoxicity
dc.titleCordycepin activates autophagy through AMPK phosphorylation to reduce abnormalities in Machado-Joseph disease models
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleDYNAMIC BRAIN FUNCTION: Towards the Understanding and Treatment of Brain Disorders
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/952422/EU
oaire.citation.endPage63
oaire.citation.issue1
oaire.citation.startPage51
oaire.citation.titleHuman Molecular Genetics
oaire.citation.volume28
oaire.fundingStreamH2020
person.familyNameMarcelo
person.familyNameNóbrega
person.givenNameAdriana
person.givenNameClévio
person.identifier.ciencia-id7613-00C2-1621
person.identifier.ciencia-idC510-7F41-BAF8
person.identifier.orcid0000-0002-7327-0170
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.rightsopenAccess
rcaap.typearticle
relation.isAuthorOfPublication3bed3cc3-e36a-445b-8d7d-4d4615ff4c4c
relation.isAuthorOfPublication725ea6f8-1363-4cee-9cf2-5ac7303b3ba9
relation.isAuthorOfPublication.latestForDiscovery3bed3cc3-e36a-445b-8d7d-4d4615ff4c4c
relation.isProjectOfPublication8ce5e5b2-8de8-466d-8dea-183955dddbe8
relation.isProjectOfPublication.latestForDiscovery8ce5e5b2-8de8-466d-8dea-183955dddbe8

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