HUNTINGTIN FIBRIL

亨廷顿原纤维

• 批准号: 8361086
• 负责人: JUDITH FRYDMAN
• 金额: $ 1.72万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8361086
• 关键词: Amino Acids; Amyloid; Apical; Binding; Cessation of life; Cryoelectron Microscopy; Disease; Disease model; Electron Microscopy; Funding; Genes; Glutamine; Grant; Huntington Disease; Molecular Chaperones; Morphology; National Center for Research Resources; Neurodegenerative Disorders; Neuronal Dysfunction; Principal Investigator; Proteins; Research; Research Infrastructure; Resources; Source; Spinocerebellar Ataxias; Time; Toxic effect; United States National Institutes of Health; chaperonin; cost; effective therapy; human Huntingtin protein; in vivo; inhibitor/antagonist; macromolecule; neurotoxicity; polyglutamine

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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 迟发性神经退行性疾病的有效治疗方法仍然难以捉摸。这些 疾病通常与不溶性淀粉样蛋白聚集体的积累有关，并且 随后的神经元功能障碍和死亡。在许多情况下，例如脊髓小脑性共济失调 和亨廷顿病 (HD)，聚集与扩展的聚谷氨酰胺有关 疾病基因中的 (polyQ) 区域，通常超出大约 40 的临界阈值 谷氨酰胺重复。分子伴侣，选择性结合非天然蛋白质和 促进其折叠或降解，已被证明可以调节聚集和毒性 在神经退行性疾病模型中。最近，弗里德曼发现真核生物 伴侣蛋白 TRiC/CCT 控制体内聚谷氨酰胺聚集和毒性，并充当 有效的聚集抑制剂。引人注目的是，我们发现 TRiC 亚基 CCT1 等 特别是 140 个氨基酸的 CCT1 顶端结构域，直接抑制聚集并 与亨廷顿病病原体（聚谷氨酰胺- 扩展亨廷顿外显子1)。 我们建议使用冷冻电镜来研究生长的亨廷顿纤维的形态 在不同时间观察 TRiC 处理后的聚集情况。