title: Calpain inhibition reduces ataxin-3 cleavage alleviating neuropathology and motor impairments in mouse models of Machado-Joseph disease.
abstract: Machado-Joseph Disease (MJD) is the most prevalent autosomal dominantly inherited cerebellar ataxia. It is caused by an expanded CAG repeat in the ATXN3 gene, which translates into a polyglutamine tract within the ataxin-3 protein. Present treatments are symptomatic and do not prevent disease progression. As calpain overactivation has been shown to contribute to mutant ataxin-3 proteolysis, translocation to the nucleus, inclusions formation and neurodegeneration, we investigated the potential role of calpain inhibition as a therapeutic strategy to alleviate MJD pathology. For this purpose, we administered orally the calpain inhibitor BDA-410 to a lentiviral mouse model of MJD. Western-blot and immunohistochemical analysis revealed the presence of N- and C-terminal mutant ataxin-3 fragments and the colocalization of large inclusions with cleaved caspase-3 in the mice brain. Oral administration of the calpain inhibitor BDA-410 decreased both fragments formation and full-length ataxin-3 levels, reduced aggregation of mutant ataxin-3 and prevented cell injury and striatal and cerebellar degeneration. Importantly, in correlation with the preserved cerebellar morphology, BDA-410 prevented motor behavioural deficits. In conclusion, BDA-410 alleviates Machado-Joseph neuropathology and may therefore be an effective therapeutic option for MJD.
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-517, Portugal Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal.
authors.forename: Ana Teresa
authors.initials: AT
authors.lastname: Simões
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-517, Portugal Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal.
authors.forename: Nélio
authors.initials: N
authors.lastname: Gonçalves
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-517, Portugal.
authors.forename: Rui Jorge
authors.initials: RJ
authors.lastname: Nobre
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-517, Portugal Faculty of Sciences and Technology, Department of Life Sciences, University of Coimbra, Coimbra 3001-401, Portugal.
authors.forename: Carlos Bandeira
authors.initials: CB
authors.lastname: Duarte
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-517, Portugal Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal luispa@cnc.uc.pt luispa@ci.uc.pt.
authors.forename: Luís
authors.initials: L
authors.lastname: Pereira de Almeida
mesh_terms: D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D017827:Machado-Joseph Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage*
chemical_list: C572617:N-1-(hydroxy(3-oxo-2-phenyl-1-cyclopropen-1-yl)methyl)-2-methylpropyl-2-benzenesulfonylamino-4-methylpentanamide; D009419:Nerve Tissue Proteins; D013449:Sulfonamides; D002154:Calpain