Please use this identifier to cite or link to this item:
https://hdl.handle.net/10316/28114
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Simões, Ana T. | - |
dc.contributor.author | Gonçalves, Nélio | - |
dc.contributor.author | Koeppen, Arnulf | - |
dc.contributor.author | Déglon, Nicole | - |
dc.contributor.author | Kügler, Sebastian | - |
dc.contributor.author | Duarte, Carlos Bandeira | - |
dc.contributor.author | Almeida, Luís Pereira de | - |
dc.date.accessioned | 2015-01-23T11:17:21Z | - |
dc.date.available | 2015-01-23T11:17:21Z | - |
dc.date.issued | 2012 | - |
dc.identifier.citation | SIMÕES, 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.issn | 0006-8950 | - |
dc.identifier.uri | https://hdl.handle.net/10316/28114 | - |
dc.description.abstract | Machado–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.iso | eng | por |
dc.publisher | Oxford University Press | por |
dc.rights | openAccess | por |
dc.subject | Machado–Joseph disease | por |
dc.subject | Spinocerebellar ataxia type 3 | por |
dc.subject | Calpastatin | por |
dc.subject | Cleavage fragment | por |
dc.subject | Proteolysis | por |
dc.title | Calpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado–Joseph disease | por |
dc.type | article | por |
degois.publication.firstPage | 2428 | por |
degois.publication.lastPage | 2439 | por |
degois.publication.location | Oxford | por |
degois.publication.title | Brain | por |
dc.relation.publisherversion | doi:10.1093/brain/aws17 | por |
dc.peerreviewed | Yes | por |
dc.identifier.doi | 10.1093/brain/aws177 | - |
degois.publication.volume | 132 | por |
uc.controloAutoridade | Sim | - |
item.openairetype | article | - |
item.languageiso639-1 | en | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.cerifentitytype | Publications | - |
item.grantfulltext | open | - |
item.fulltext | Com Texto completo | - |
crisitem.author.researchunit | CNC - Center for Neuroscience and Cell Biology | - |
crisitem.author.researchunit | CNC - Center for Neuroscience and Cell Biology | - |
crisitem.author.researchunit | CNC - Center for Neuroscience and Cell Biology | - |
crisitem.author.researchunit | CIBB - Center for Innovative Biomedicine and Biotechnology | - |
crisitem.author.orcid | 0000-0003-3305-485X | - |
crisitem.author.orcid | 0000-0002-1474-0208 | - |
crisitem.author.orcid | 0000-0001-5831-3307 | - |
Appears in Collections: | FFUC- Artigos em Revistas Internacionais I&D CNC - Artigos em Revistas Internacionais FCTUC Ciências da Vida - Artigos em Revistas Internacionais |
Files in This Item:
File | Description | Size | Format | |
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Calpastatin.pdf | 400.98 kB | Adobe PDF | View/Open |
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