HUNTINGTIN FIBRIL

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 迟发性神经退行性疾病的有效治疗仍然难以捉摸。这些疾病通常与不溶性淀粉样蛋白聚集体的积累以及随后的神经元功能障碍和死亡有关。在许多情况下，例如脊髓小脑性共济失调和亨廷顿病（HD），聚集与疾病基因中的扩展的多聚谷氨酰胺（polyQ）束相关，通常超过约40个谷氨酰胺重复的临界阈值。分子伴侣，选择性地结合非天然蛋白质，并促进其折叠或降解，已被证明可以调节神经退行性疾病模型中的聚集和毒性。最近，Frydman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，并作为聚集的有效抑制剂。引人注目的是，我们发现TRiC亚基CCT 1，更具体地说是140个氨基酸的CCT 1顶端结构域，直接抑制与亨廷顿病的病原体（多聚谷氨酰胺扩展的亨廷顿蛋白外显子1）相关的聚集和神经毒性。 我们建议使用cryoEM来研究在不同时间生长的亨廷顿原核细胞的形态，并观察用TRiC处理后的聚集。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.