Synaptic toxicity of Huntington disease protein

亨廷顿病蛋白的突触毒性

基本信息

批准号：
6509964
负责人：
XIAO-JIANG LI
金额：
$ 29.49万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-05-01 至 2006-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6509964
关键词：
Huntington's disease PC12 cells affinity chromatography axon chimeric proteins homopeptide immunocytochemistry immunoelectron microscopy laboratory rat mutant nerve /myelin protein neuropathology neuropil neurotransmitter transport synaptic vesicles western blottings yeast two hybrid system

项目摘要

DESCRIPTION: (Verbatim from the Applicant's Abstract) Polyglutamine expansion causes Huntington's disease (HD) and seven other inherited neurodegenerative disorders. A central question about these diseases is how polyglutamine expansion induces the selective neuropathology in each disorder. In HD, selective neuronal loss occurs in the striatum and the deep layers of the cerebral cortex while the disease protein huntingtin is widely expressed. Recent studies have shown that polyglutamine expansion causes N-terminal huntingtin to aggregate, to accumulate in the nucleus, and to interact abnormally with other proteins. However, intranuclear huntingtin aggregates are not causally associated with neurodegeneration. Our recent fmdings indicate that mutant huntingtin also forms aggregates in neuropil and axonal terminals and suggest that the formation of neuropil aggregates is highly correlated with neurological symptoms in HD mice. Since huntingtin aggregates are composed of N-terminal fragments of mutant huntingtin, we hypothesize that N-terminal mutant huntingtin in the neuropil induces synaptic dysfunction that contributes to the early neuropathology of HD. To test this idea, we will (1) examine whether N-terminal huntingtin fragments preferentially form axonal aggregates in HD-affected striatal neurons, (2) study whether mutant N-terminal huntingtin abnormally binds to synaptic vesicles, and (3) investigate whether N-terminal mutant huntingtin affects neurotransmitter uptake or release of synaptic vesicles. These studies aim to provide insights into the mechanism of the specific neuropathology of HD and to help develop an effective strategy for the treatment of HD.

描述：（逐字摘自申请人摘要）聚谷氨酰胺扩增导致亨廷顿病 (HD) 和其他七种遗传性神经退行性疾病失调。关于这些疾病的一个核心问题是聚谷氨酰胺如何扩张会诱发每种疾病的选择性神经病理学。在高清中，选择性神经元丢失发生在纹状体和深层而疾病蛋白亨廷顿蛋白在大脑皮层广泛表达。最近的研究表明，聚谷氨酰胺扩增会导致 N 末端亨廷顿蛋白聚集、在细胞核中积累并相互作用与其他蛋白质异常。然而，核内亨廷顿蛋白聚集体与神经退行性疾病没有因果关系。我们最近的发现表明突变亨廷顿蛋白也在神经纤维和轴突末端形成聚集体并表明神经纤维聚集体的形成与 HD 小鼠的神经系统症状。由于亨廷顿聚集体由突变亨廷顿蛋白的 N 端片段，我们假设 N 端神经纤维中的突变亨廷顿蛋白会诱导突触功能障碍，从而导致 HD 的早期神经病理学。为了检验这个想法，我们将 (1) 检查 N端亨廷顿片段是否优先形成轴突聚集体在HD影响的纹状体神经元中，（2）研究突变的N末端亨廷顿蛋白是否与突触小泡异常结合，并且（3）研究 N 末端是否突变亨廷顿蛋白影响神经递质的摄取或突触的释放囊泡。这些研究旨在深入了解该机制 HD 的特定神经病理学并帮助制定有效的策略 HD 的治疗。