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

被引:46
|
作者
Simoes, Ana Teresa [1 ,2 ]
Goncalves, Nelio [1 ,2 ]
Nobre, Rui Jorge [1 ]
Duarte, Carlos Bandeira [1 ,3 ]
de Almeida, Luis Pereira [1 ,2 ]
机构
[1] Univ Coimbra, CNC Ctr Neurosci & Cell Biol, P-3004517 Coimbra, Portugal
[2] Univ Coimbra, Fac Pharm, P-3000548 Coimbra, Portugal
[3] Univ Coimbra, Dept Life Sci, Fac Sci & Technol, P-3001401 Coimbra, Portugal
关键词
POLYGLUTAMINE-EXPANDED ATAXIN-3; POSITRON-EMISSION-TOMOGRAPHY; SPINOCEREBELLAR ATAXIA; MUTANT HUNTINGTIN; INTRANUCLEAR INCLUSIONS; NUCLEAR-LOCALIZATION; LENTIVIRAL VECTOR; NEURONAL CELLS; RAT MODEL; IN-VITRO;
D O I
10.1093/hmg/ddu209
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:4932 / 4944
页数:13
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