Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin
Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin
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DOI：
10.1016/j.cell.2006.04.026
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发表时间：
2006-06-16
期刊：
影响因子：
64.5
通讯作者：
Hayden, Michael R.
中科院分区：
文献类型：
--
作者：
Graham, Rona K.;Deng, Yu;Hayden, Michael R.
在体外对亨廷顿蛋白（htt）的裂解进行了表征，半胱天蛋白酶裂解片段的积累代表了亨廷顿病（HD）患者大脑的早期病理改变。然而，htt蛋白水解与HD发病机制之间的关系尚不清楚。为了确定htt的caspase切割是否是HID神经元功能障碍和选择性神经退行性变的关键事件，我们制造了表达caspase-3和caspase-6抗性突变htt的YAC小鼠。表达突变体htt的小鼠能抵抗caspase-6而非caspase-3的切割，维持正常的神经元功能，不发生纹状体神经变性。此外，caspase-6耐药突变htt小鼠可免受NMDA、喹啉酸（QA）和staurosporine等多种应激源诱导的神经毒性。这些结果与caspase-6切割位点的htt蛋白水解是介导神经元功能障碍和神经变性的重要事件一致，并突出了htt蛋白水解的重要作用；和HID的兴奋性毒性。
Cleavage of huntingtin (htt) has been characterized in vitro, and accumulation of caspase cleavage fragments represents an early pathological change in brains of Huntington's disease (HD) patients. However, the relationship between htt proteolysis and the pathogenesis of HD is unknown. To determine whether caspase cleavage of htt is a key event in the neuronal dysfunction and selective neurodegeneration in HID, we generated YAC mice expressing caspase-3- and caspase-6- resistant mutant htt. Mice expressing mutant htt, resistant to cleavage by caspase-6 but not caspase-3, maintain normal neuronal function and do not develop striatal neurodegeneration. Furthermore, caspase-6-resistant mutant htt mice are protected against neurotoxicity induced by multiple stressors including NMDA, quinolinic acid (QA), and staurosporine. These results are consistent with proteolysis of htt at the caspase-6 cleavage site being an important event in mediating neuronal dysfunction and neurodegeneration and highlight the significant role of htt proteolysis; and excitotoxicity in HID.