Please use this identifier to cite or link to this item: http://hdl.handle.net/10316/28114
DC FieldValueLanguage
dc.contributor.authorSimões, Ana T.-
dc.contributor.authorGonçalves, Nélio-
dc.contributor.authorKoeppen, Arnulf-
dc.contributor.authorDéglon, Nicole-
dc.contributor.authorKügler, Sebastian-
dc.contributor.authorDuarte, Carlos Bandeira-
dc.contributor.authorAlmeida, Luís Pereira de-
dc.date.accessioned2015-01-23T11:17:21Z-
dc.date.available2015-01-23T11:17:21Z-
dc.date.issued2012-
dc.identifier.citationSIMÕES, Ana T; GONÇALVES, Nélio; KOEPPEN, Arnulf; DÉGLON, Nicole; KÜGLER, Sebastian; DUARTE, Carlos Bandeira; ALMEIDA, Luís Pereira de - Calpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado–Joseph disease. “Brain”. ISSN: 0006-8950. 135 (2012) 2428–243.por
dc.identifier.issn0006-8950-
dc.identifier.urihttp://hdl.handle.net/10316/28114-
dc.description.abstractMachado–Joseph disease is the most frequently found dominantly-inherited cerebellar ataxia. Over-repetition of a CAG trinucleotide in the MJD1 gene translates into a polyglutamine tract within the ataxin 3 protein, which upon proteolysis may trigger Machado–Joseph disease. We investigated the role of calpains in the generation of toxic ataxin 3 fragments and pathogenesis of Machado–Joseph disease. For this purpose, we inhibited calpain activity in mouse models of Machado–Joseph disease by overexpressing the endogenous calpain-inhibitor calpastatin. Calpain blockage reduced the size and number of mutant ataxin 3 inclusions, neuronal dysfunction and neurodegeneration. By reducing fragmentation of ataxin 3, calpastatin overexpression modified the subcellular localization of mutant ataxin 3 restraining the protein in the cytoplasm, reducing aggregation and nuclear toxicity and overcoming calpastatin depletion observed upon mutant ataxin 3 expression. Our findings are the first in vivo proof that mutant ataxin 3 proteolysis by calpains mediates its translocation to the nucleus, aggregation and toxicity and that inhibition of calpains may provide an effective therapy for Machado–Joseph disease.por
dc.language.isoengpor
dc.publisherOxford University Presspor
dc.rightsopenAccesspor
dc.subjectMachado–Joseph diseasepor
dc.subjectSpinocerebellar ataxia type 3por
dc.subjectCalpastatinpor
dc.subjectCleavage fragmentpor
dc.subjectProteolysispor
dc.titleCalpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado–Joseph diseasepor
dc.typearticlepor
degois.publication.firstPage2428por
degois.publication.lastPage2439por
degois.publication.locationOxfordpor
degois.publication.titleBrainpor
dc.relation.publisherversiondoi:10.1093/brain/aws17por
dc.peerreviewedYespor
dc.identifier.doi10.1093/brain/aws177-
degois.publication.volume132por
uc.controloAutoridadeSim-
item.fulltextCom Texto completo-
item.grantfulltextopen-
item.languageiso639-1en-
crisitem.author.deptFaculty of Sciences and Technology-
crisitem.author.deptFaculty of Pharmacy-
crisitem.author.parentdeptUniversity of Coimbra-
crisitem.author.researchunitCNC - Center for Neuroscience and Cell Biology-
crisitem.author.researchunitCNC - Center for Neuroscience and Cell Biology-
crisitem.author.researchunitCNC - Center for Neuroscience and Cell Biology-
crisitem.author.orcid0000-0003-3305-485X-
crisitem.author.orcid0000-0002-1474-0208-
crisitem.author.orcid0000-0001-5831-3307-
Appears in Collections:FFUC- Artigos em Revistas Internacionais
I&D CNC - Artigos em Revistas Internacionais
FCTUC Ciências da Vida - Artigos em Revistas Internacionais
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