Please use this identifier to cite or link to this item:
https://hdl.handle.net/10316/28131
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. | URI: | https://hdl.handle.net/10316/28131 | 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 |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
14_HumMolGenet_Simões et al(1).pdf | 1.39 MB | Adobe PDF | View/Open |
SCOPUSTM
Citations
49
checked on Sep 30, 2024
WEB OF SCIENCETM
Citations
45
checked on Oct 2, 2024
Page view(s) 50
485
checked on Oct 8, 2024
Download(s)
247
checked on Oct 8, 2024
Google ScholarTM
Check
Altmetric
Altmetric
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.