Please use this identifier to cite or link to this item: http://hdl.handle.net/1822/44952

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dc.contributor.authorSilva, Sara Carina Duartepor
dc.contributor.authorFernandes, Anabela Silvapor
dc.contributor.authorCarvalho, Andreia Alexandra Nevespor
dc.contributor.authorCunha, Carina Isabel Soarespor
dc.contributor.authorCastro, Andreia Cristiana Teixeirapor
dc.contributor.authorMaciel, P.por
dc.date.accessioned2017-03-10T11:38:06Z-
dc.date.available2017-03-10T11:38:06Z-
dc.date.issued2016-01-
dc.identifier.citationDuarte-Silva, S., Silva-Fernandes, A., Neves-Carvalho, A., Soares-Cunha, C., Teixeira-Castro, A., & Maciel, P. (2016). Combined therapy with m-TOR-dependent and -independent autophagy inducers causes neurotoxicity in a mouse model of Machado-Joseph disease. Neuroscience, 313, 162-173. doi: 10.1016/j.neuroscience.2015.11.030por
dc.identifier.issn0306-4522por
dc.identifier.urihttp://hdl.handle.net/1822/44952-
dc.description.abstractA major pathological hallmark in several neurodegenerative disorders, like polyglutamine disorders (polyQ), including Machado-Joseph disease (MJD), is the formation of protein aggregates. MJD is caused by a CAG repeat expansion in the ATXN3 gene, resulting in an abnormal protein, which is prone to misfolding and forms cytoplasmic and nuclear aggregates within neurons, ultimately inducing neurodegeneration. Treatment of proteinopathies with drugs that up-regulate autophagy has shown promising results in models of polyQ diseases. Temsirolimus (CCI-779) inhibits the mammalian target of rapamycin (m-TOR), while lithium chloride (LiCl) acts by inhibiting inositol monophosphatase, both being able to induce autophagy. We have previously shown that chronic treatment with LiCl (10.4 mg/kg) had limited effects in a transgenic MJD mouse model. Also, others have shown that CCI-779 had mild positive effects in a different mouse model of the disease. It has been suggested that the combination of mTOR-dependent and -independent autophagy inducers could be a more effective therapeutic approach. To further explore this avenue toward therapy, we treated CMVMJD135 transgenic mice with a conjugation of CCI-779 and LiCl, both at concentrations known to induce autophagy and not to be toxic. Surprisingly, this combined treatment proved to be deleterious to both wild-type (wt) and transgenic animals, failing to rescue their neurological symptoms and actually exerting neurotoxic effects. These results highlight the possible dangers of manipulating autophagy in the nervous system and suggest that a better understanding of the potential disruption in the autophagy pathway in MJD is required before successful long-term autophagy modulating therapies can be developed.por
dc.description.sponsorshipFundação para a Ciência e Tecnologia through the projects [FEDER/FCT, POCI/SAU-MMO/60412/2004], [PTDC/SAU-GMG/64076/2006]. This work was supported by Fundação para a Ciência e Tecnologiapor
dc.language.isoengpor
dc.publisherElsevierpor
dc.relationinfo:eu-repo/grantAgreement/FCT/POCI/60412/PTpor
dc.relationinfo:eu-repo/grantAgreement/FCT/5876-PPCDTI/64076/PTpor
dc.relationinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F78388%2F2011/PTpor
dc.relationinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBPD%2F91562%2F2012/PTpor
dc.relationinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F51059%2F2010/PTpor
dc.relationinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F51992%2F2012/PTpor
dc.relationinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBPD%2F79469%2F2011/PTpor
dc.rightsopenAccesspor
dc.subjectPolyglutamine diseasespor
dc.subjectAnimal modelspor
dc.subjectAtaxiapor
dc.subjectBehaviorpor
dc.subjectTherapypor
dc.subjectAutophagypor
dc.titleCombined therapy with m-TOR-dependent and -independent autophagy inducers causes neurotoxicity in a mouse model of Machado-Joseph diseasepor
dc.typearticle-
dc.peerreviewedyespor
dc.relation.publisherversionhttp://www.sciencedirect.com/science/article/pii/S0306452215010192por
sdum.publicationstatusinfo:eu-repo/semantics/publishedVersionpor
oaire.citationStartPage162por
oaire.citationEndPage173por
oaire.citationTitleNeurosciencepor
oaire.citationVolume313por
dc.date.updated2017-02-14T11:34:10Z-
dc.identifier.doi10.1016/j.neuroscience.2015.11.030por
dc.identifier.pmid26601773por
dc.subject.fosCiências Médicas::Medicina Básicapor
dc.subject.wosScience & Technologypor
sdum.journalNeurosciencepor
Appears in Collections:ICVS - Artigos em Revistas Internacionais com Referee

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