Altered cholesterol homeostasis contributes to enhanced excitotoxicity in Huntington's disease
Altered cholesterol homeostasis contributes to enhanced excitotoxicity in Huntington's disease
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DOI：
10.1111/j.1471-4159.2010.06912.x
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发表时间：
2010-10-01
影响因子：
4.7
通讯作者：
Alberch, Jordi
中科院分区：
文献类型：
--
作者：
del Toro, Daniel;Xifro, Xavier;Alberch, Jordi
最近的研究表明胆固醇稳态的改变可能与亨廷顿病的病理生理学有关。为了了解潜在的机制，在这里，我们使用了双光子显微镜，落射荧光和生物化学方法的组合，以可视化和量化表达突变亨廷顿蛋白的细胞培养物中的脂质分布。这种表达促进细胞和小鼠模型以及HD影响的人脑中的脂质失衡和胆固醇积累。有趣的是，表达突变亨廷顿蛋白的细胞在其质膜中也显示出更高含量的有序结构域。这些发现与细胞表面高水平的小窝蛋白-1和鞘糖脂GM 1相关，这是两种明确的胆固醇富集结构域标志物。此外，表达突变亨廷顿蛋白的细胞表现出增加的本地化的NMDA受体与胆固醇富集域，有助于增加NMDA受体的敏感性兴奋毒性损伤。用辛伐他汀或β-环糊精（两种降胆固醇药物）治疗，降低了细胞表面有序结构域的含量，从而保护细胞免受NMDA介导的兴奋性毒性。总之，我们的研究结果表明，突变亨廷顿蛋白产生胆固醇的积累，并改变其细胞分布，有助于NMDA介导的兴奋性毒性。服用可以恢复这种效果的药物（例如辛伐他汀）可能有助于HD的治疗。
P>Recent findings suggest that altered cholesterol homeostasis may contribute to the pathophysiology of Huntington's disease (HD). To understand the underlying mechanisms, here we used a combination of two-photon microscopy, epifluorescence, and biochemical methods to visualize and quantify lipid distribution in cell cultures expressing mutant huntingtin. Such expression promotes lipid imbalance, and cholesterol accumulation in cellular and murine models and in HD-affected human brains. Interestingly, cells expressing mutant huntingtin also showed higher content of ordered domains in their plasma membranes. These findings correlated with high levels of caveolin-1 and glycosphingolipid GM1, two well-defined markers of cholesterol-enriched domains, at the cell surface. In addition, cells expressing mutant huntingtin showed increased localization of NMDA receptors with cholesterol-enriched domains, contributing to increased NMDA receptor susceptibility to excitotoxic insults. Treatment with simvastatin or beta-cyclodextrin, two cholesterol-lowering drugs, reduced the content of ordered domains at the cell surface, which in turn, protected cells against NMDA-mediated excitotoxicity. Taken together, our results indicate that mutant huntingtin produces accumulation of cholesterol and alters its cellular distribution that contributes to NMDA-mediated excitotoxicity. Administration of drugs that recover this effect, such as simvastatin could be beneficial for the treatment of HD.