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Title: Calpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado–Joseph disease
Authors: Simões, Ana T. 
Gonçalves, Nélio 
Koeppen, Arnulf 
Déglon, Nicole 
Kügler, Sebastian 
Duarte, Carlos Bandeira 
Almeida, Luís Pereira de 
Keywords: Machado–Joseph disease; Spinocerebellar ataxia type 3; Calpastatin; Cleavage fragment; Proteolysis
Issue Date: 2012
Publisher: Oxford University Press
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.
Serial title, monograph or event: Brain
Volume: 132
Place of publication or event: Oxford
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.
ISSN: 0006-8950
DOI: 10.1093/brain/aws177
Rights: openAccess
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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