Haacke Annette, Hartl F Ulrich, Breuer Peter
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
J Biol Chem. 2007 Jun 29;282(26):18851-6. doi: 10.1074/jbc.M611914200. Epub 2007 May 8.
The formation of intraneuronal inclusions is a common feature of neurodegenerative polyglutamine disorders, including Spinocerebellar ataxia type 3. The mechanism that triggers inclusion formation in these typically late onset diseases has remained elusive. However, there is increasing evidence that proteolytic fragments containing the expanded polyglutamine segment are critically required to initiate the aggregation process. We analyzed ataxin-3 proteolysis in neuroblastoma cells and in vitro and show that calcium-dependent calpain proteases generate aggregation-competent ataxin-3 fragments. Co-expression of the highly specific cellular calpain inhibitor calpastatin abrogated fragmentation and the formation of inclusions in cells expressing pathological ataxin-3. These findings suggest a critical role of calpains in the pathogenesis of Spinocerebellar ataxia type 3.
神经元内包涵体的形成是神经退行性多聚谷氨酰胺疾病的一个常见特征，包括3型脊髓小脑共济失调。在这些通常发病较晚的疾病中，触发包涵体形成的机制一直难以捉摸。然而，越来越多的证据表明，含有扩展多聚谷氨酰胺片段的蛋白水解片段对于启动聚集过程至关重要。我们分析了神经母细胞瘤细胞和体外的ataxin-3蛋白水解，结果表明钙依赖性钙蛋白酶产生具有聚集能力的ataxin-3片段。高特异性细胞钙蛋白酶抑制剂钙蛋白酶抑制蛋白的共表达消除了表达病理性ataxin-3的细胞中的片段化和包涵体形成。这些发现表明钙蛋白酶在3型脊髓小脑共济失调的发病机制中起关键作用。
