Calpain inhibition reduces ataxin-3 cleavage alleviating neuropathology and motor impairments in mouse models of machado-Joseph disease

Ana Teresa Simões, Nélio Gonçalves, Rui Jorge Nobre, Carlos Bandeira Duarte, Luís Pereira de Almeida*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)

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.
Original languageEnglish
Article numberddu209
Pages (from-to)4932-4944
Number of pages13
JournalHuman Molecular Genetics
Volume23
Issue number18
DOIs
Publication statusPublished - Sep 2014
Externally publishedYes

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