Calpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado-Joseph disease.
Calpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado-Joseph disease.
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DOI：
10.1093/brain/aws177
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发表时间：
2012-08
期刊：
影响因子：
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通讯作者：
A. Simões;N. Gonçalves;A. Koeppen;N. Déglon;S. Kügler;C. Duarte;L. Pereira de Almeida
中科院分区：
文献类型：
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作者：
A. Simões;N. Gonçalves;A. Koeppen;N. Déglon;S. Kügler;C. Duarte;L. Pereira de Almeida
Machado-Joseph病是最常见的显性遗传性小脑共济失调。MJD 1基因中CAG三核苷酸的过度重复翻译成共济失调蛋白3蛋白内的多聚谷氨酰胺束，其在蛋白水解时可能触发Machado-Joseph病。我们研究了钙蛋白酶在产生毒性共济失调蛋白3片段和Machado-Joseph病发病机制中的作用。为此，我们通过过表达内源性钙蛋白酶抑制剂钙蛋白酶抑制剂来抑制马查多-约瑟夫病小鼠模型中的钙蛋白酶活性。钙蛋白酶阻断减少了突变型共济失调蛋白3包涵体的大小和数量，神经元功能障碍和神经变性。通过减少共济失调蛋白3的片段化，钙蛋白酶抑制蛋白过表达改变了突变型共济失调蛋白3的亚细胞定位，抑制了蛋白质在细胞质中的聚集和核毒性，并克服了突变型共济失调蛋白3表达后观察到的钙蛋白酶抑制蛋白耗竭。我们的研究结果是第一个在体内证明，突变型共济失调蛋白3蛋白水解钙蛋白酶介导其易位到核，聚集和毒性，抑制钙蛋白酶可能提供一种有效的治疗Machado-Joseph病。
Machado-Joseph disease is the most frequently found dominantly-inherited cerebellar ataxia. Over-repetition of a CAG trinucleotide in the MJD1 gene translates into a polyglutamine tract within the ataxin 3 protein, which upon proteolysis may trigger Machado-Joseph disease. We investigated the role of calpains in the generation of toxic ataxin 3 fragments and pathogenesis of Machado-Joseph disease. For this purpose, we inhibited calpain activity in mouse models of Machado-Joseph disease by overexpressing the endogenous calpain-inhibitor calpastatin. Calpain blockage reduced the size and number of mutant ataxin 3 inclusions, neuronal dysfunction and neurodegeneration. By reducing fragmentation of ataxin 3, calpastatin overexpression modified the subcellular localization of mutant ataxin 3 restraining the protein in the cytoplasm, reducing aggregation and nuclear toxicity and overcoming calpastatin depletion observed upon mutant ataxin 3 expression. Our findings are the first in vivo proof that mutant ataxin 3 proteolysis by calpains mediates its translocation to the nucleus, aggregation and toxicity and that inhibition of calpains may provide an effective therapy for Machado-Joseph disease.