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Title: Calpain inhibition reduces ataxin-3 cleavage alleviating neuropathology and motor impairments in mouse models of Machado-Joseph disease
Authors: Simões, Ana Teresa 
Gonçalves, Nélio 
Nobre, Rui Jorge 
Duarte, Carlos Bandeira 
Almeida, Luís Pereira de 
Issue Date: 2014
Publisher: Oxford University Press
Citation: SIMÕES, Ana Teresa; GONÇALVES, Nélio; NOBRE, Rui Jorge, DUARTE, Carlos Bandeira; ALMEIDA, Luís Pereira de - Calpain inhibition reduces ataxin-3 cleavage alleviating neuropathology and motor impairments in mouse models of Machado-Joseph disease. “Human Molecular Genetics”. ISSN: 0964-6906. 23:18 (2014) 4932–4944. Doi: 10.1093/hmg/ddu209>.
Serial title, monograph or event: Human Molecular Genetics
Volume: 23
Issue: 18
Place of publication or event: Oxford
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.
ISSN: 0964-6906
DOI: 10.1093/hmg/ddu209
Rights: embargoedAccess
Appears in Collections:FFUC- Artigos em Revistas Internacionais
I&D CNC - Artigos em Revistas Internacionais
FCTUC Ciências da Vida - Artigos em Revistas Internacionais

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