Journal Article

Calpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado–Joseph disease

Ana T. Simões, Nélio Gonçalves, Arnulf Koeppen, Nicole Déglon, Sebastian Kügler, Carlos Bandeira Duarte and Luís Pereira de Almeida

in Brain

Published on behalf of The Guarantors of Brain

Volume 135, issue 8, pages 2428-2439
Published in print August 2012 | ISSN: 0006-8950
Published online July 2012 | e-ISSN: 1460-2156 | DOI:

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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.

Keywords: Machado–Joseph disease; spinocerebellar ataxia type 3; proteolysis; calpastatin; cleavage fragment

Journal Article.  6816 words.  Illustrated.

Subjects: Neurology ; Neuroscience