HUNTINGTIN FIBRIL

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 迟发性神经退行性疾病的有效治疗方法仍然难以找到。这些 疾病通常与不可溶的淀粉样聚集物的积累有关，并且 随之而来的神经元功能障碍和死亡。在许多情况下，如脊髓小脑性共济失调 和亨廷顿病(HD)，聚集与扩张的聚谷氨酰胺有关 (PolyQ)疾病基因中的区段，通常超过约40的临界阈值 谷氨酰胺会重复。分子伴侣，选择性地结合非天然蛋白质和 促进它们的折叠或降解，已被证明调节聚集和毒性 在神经退行性疾病模型中。最近，弗莱德曼发现真核生物 伴侣蛋白TRIC/CCT在体内控制聚谷氨酰胺聚集和毒性，并作为一种 有效的聚集性抑制因子。令人惊讶的是，我们发现了tra亚单位CCT1，以及更多 特别是140个氨基酸的CCT1顶端结构域，直接抑制聚集和 亨廷顿S病(多谷氨酰胺)的神经毒性 扩大的亨廷顿蛋白外显子1)。 我们建议使用低温电子显微镜来研究生长的亨廷顿林堡的形态。 在不同的时间，并查看TIC治疗后的聚集。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. An effective therapy for late-onset neurodegenerative diseases remains elusive. These disorders are often associated with the accumulation of insoluble amyloid aggregates, and subsequent neuronal dysfunction and death. In many cases, such as Spinocerebellar Ataxia and Huntington's disease (HD), aggregation is associated with expanded polyglutamine (polyQ) tracts in the disease gene, usually beyond a critical threshold of approximately 40 glutamine repeats. Molecular chaperones, which selectively bind non-native proteins and facilitate their folding or degradation, have been shown to modulate aggregation and toxicity in neurodegenerative disease models. Recently, Frydman found that the eukaryotic chaperonin TRiC/CCT controls polyglutamine aggregation and toxicity in vivo and acts as a potent inhibitor of aggregation. Strikingly, we found that TRiC subunit CCT1, and more specifically the 140 amino acid CCT1 apical domain, directly inhibits the aggregation and neurotoxicity associated with the causative agent of Huntington?s disease (polyglutamine- expanded huntingtin exon1). We propose to use cryoEM to study the morphology of the Huntingtin firbils which are grown at different times and see the aggregation upon treatment with TRiC.