title: Calpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado-Joseph disease.
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.
authors: Centre for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
authors: Ana T
authors: AT
authors: Simões
authors: Nélio
authors: N
authors: Gonçalves
authors: Arnulf
authors: A
authors: Koeppen
authors: Nicole
authors: N
authors: Déglon
authors: Sebastian
authors: S
authors: Kügler
authors: Carlos Bandeira
authors: CB
authors: Duarte
authors: Luís
authors: L
authors: Pereira de Almeida
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics*; D000328:Adult; D000818:Animals; D000067699:Ataxin-3; D001923:Brain Chemistry / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000502:physiology*; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology; D006801:Humans; D017827:Machado-Joseph Disease / Q000201:enzymology / Q000378:metabolism* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D006023:Glycoproteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D014157:Transcription Factors; C039304:calpain inhibitors; C033668:calpastatin; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse; D002154:Calpain