Utilize este identificador para referenciar este registo:
https://hdl.handle.net/10316/28131
Título: | Calpain inhibition reduces ataxin-3 cleavage alleviating neuropathology and motor impairments in mouse models of Machado-Joseph disease | Autor: | Simões, Ana Teresa Gonçalves, Nélio Nobre, Rui Jorge Duarte, Carlos Bandeira Almeida, Luís Pereira de |
Data: | 2014 | Editora: | Oxford University Press | Citação: | 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>. | Título da revista, periódico, livro ou evento: | Human Molecular Genetics | Volume: | 23 | Número: | 18 | Local de edição ou do evento: | Oxford | Resumo: | 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. | URI: | https://hdl.handle.net/10316/28131 | ISSN: | 0964-6906 | DOI: | 10.1093/hmg/ddu209 | Direitos: | embargoedAccess |
Aparece nas coleções: | FFUC- Artigos em Revistas Internacionais I&D CNC - Artigos em Revistas Internacionais FCTUC Ciências da Vida - Artigos em Revistas Internacionais |
Ficheiros deste registo:
Ficheiro | Descrição | Tamanho | Formato | |
---|---|---|---|---|
14_HumMolGenet_Simões et al(1).pdf | 1.39 MB | Adobe PDF | Ver/Abrir |
Citações SCOPUSTM
49
Visto em 19/ago/2024
Citações WEB OF SCIENCETM
45
Visto em 2/ago/2024
Visualizações de página 50
472
Visto em 27/ago/2024
Downloads
241
Visto em 27/ago/2024
Google ScholarTM
Verificar
Altmetric
Altmetric
Todos os registos no repositório estão protegidos por leis de copyright, com todos os direitos reservados.