期刊
HUMAN MOLECULAR GENETICS
卷 23, 期 18, 页码 4932-4944出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddu209
关键词
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资金
- funds FEDER through the Competitive Factors Operational Program-COMPETE
- national funds through the Portuguese Foundation for Science and Technology [PTDC/SAU-NEU/099307/2008, PEst-C/SAU/LA0001/2013-2014, E-Rare-2]
- ERA-Net for Research on Rare Diseases
- Richard Chin and Lilly Lock Machado-Joseph disease Research Fund and Programa Mais Centro [CENTRO-07-ST24-FEDER-002002, 002006, 002008]
- Portuguese Foundation for Science and Technology [SFRH/BPD/87341/2012, SFRH/BD/38636/2007, SFRH/BPD/66705/2009]
- Fundação para a Ciência e a Tecnologia [PTDC/SAU-NEU/099307/2008, SFRH/BD/38636/2007, SFRH/BPD/87341/2012] Funding Source: FCT
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 over-activation 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.
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