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

• DOI: 10.1093/brain/aws177
• Publication Date: 2012-07-28T12:53:37Z
• Authors: A. T. Simoes; N. Goncalves; A. Koeppen; N. Deglon; S. Kugler; C. B. Duarte; L. Pereira de Alm...
• Keywords: Adult; Male; 0301 basic medicine; Active Transport, Cell Nucleus; Mice, Transgenic; Mice; 03 medical and health sciences; Spinocerebellar ataxia type 3; Animals; Humans; Ataxin-3; Glycoproteins; Brain Chemistry; 0303 health sciences; Calpain; Calcium-Binding Proteins; Nuclear Proteins; Machado-Joseph Disease; Middle Aged; 3. Good health; Mice, Inbred C57BL; Cleavage fragment; Neuroprotective Agents; Mutation; Proteolysis; Female; Calpastatin; Machado–Joseph disease

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.