Wild-type huntingtin protects neurons from excitotoxicity
Wild-type huntingtin protects neurons from excitotoxicity
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DOI：
10.1111/j.1471-4159.2005.03605.x
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发表时间：
2006-02-01
影响因子：
4.7
通讯作者：
Hayden, MR
中科院分区：
文献类型：
--
作者：
Leavitt, BR;van Raamsdonk, JM;Hayden, MR
亨廷顿蛋白是半胱天冬酶底物，半胱天冬酶介导的蛋白水解导致正常亨廷顿蛋白功能的丧失可能在亨廷顿病的发病机制中发挥作用。在这里，我们测试了这样的假设：增加亨廷顿蛋白水平可以保护纹状体神经元免受 NMDA 受体介导的兴奋性毒性的影响。与培养的来自非转基因 FVB/N 同窝小鼠和表达突变型人亨廷顿蛋白的 YAC72 小鼠的纹状体神经元相比，培养的来自过表达全长野生型亨廷顿蛋白的酵母人工染色体 (YAC)18 转基因小鼠的纹状体神经元显着免受细胞凋亡和 caspase-3 激活。纹状体内注射喹啉酸诱导的 NMDA 受体激活引发了小鼠纹状体内一种形式的凋亡性神经变性，这与神经元和星形胶质细胞中亨廷顿蛋白的 caspase-3 裂解、全长亨廷顿蛋白水平降低以及亨廷顿蛋白 N 末端 caspase 裂解产物的产生有关。在体内，野生型亨廷顿蛋白在 YAC18 转基因小鼠中的过度表达对 NMDA 受体介导的细胞凋亡性神经变性具有显着的保护作用。这些数据提供了体外和体内证据，表明亨廷顿蛋白可以调节急性兴奋毒性应激后神经元存活和死亡之间的平衡，并且亨廷顿蛋白的水平可以调节神经元对兴奋毒性神经变性的敏感性。我们建议进一步研究亨廷顿蛋白的抗凋亡功能将有助于我们了解亨廷顿病的发病机制，并为纹状体神经元对兴奋性毒性细胞死亡的选择性脆弱性提供见解。
Huntingtin is a caspase substrate, and loss of normal huntingtin function resulting from caspase-mediated proteolysis may play a role in the pathogenesis of Huntington disease. Here we tested the hypothesis that increasing huntingtin levels protect striatal neurons from NMDA receptor-mediated excitotoxicity. Cultured striatal neurons from yeast artificial chromosome (YAC)18 transgenic mice over-expressing full-length wild-type huntingtin were dramatically protected from apoptosis and caspase-3 activation compared with cultured striatal neurons from non-transgenic FVB/N littermates and YAC72 mice expressing mutant human huntingtin. NMDA receptor activation induced by intrastriatal injection of quinolinic acid initiated a form of apoptotic neurodegeneration within the striatum of mice that was associated with caspase-3 cleavage of huntingtin in neurons and astrocytes, decreased levels of full-length huntingtin, and the generation of a specific N-terminal caspase cleavage product of huntingtin. In vivo, over-expression of wild-type huntingtin in YAC18 transgenic mice conferred significant protection against NMDA receptor-mediated apoptotic neurodegeneration. These data provide in vitro and in vivo evidence that huntingtin may regulate the balance between neuronal survival and death following acute excitotoxic stress, and that the levels of huntingtin may modulate neuronal sensitivity to excitotoxic neurodegeneration. We suggest that further study of huntingtin's anti-apoptotic function will contribute to our understanding of the pathogenesis of Huntingdon's disease and provide insights into the selective vulnerability of striatal neurons to excitotoxic cell death.