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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子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， 随后的神经元功能障碍和死亡。在许多情况下，如脊髓小脑共济失调 和亨廷顿病（HD），聚集与扩展的多聚谷氨酰胺有关 在疾病基因中的polyQ片段，通常超过约40的临界阈值 谷氨酰胺重复序列。分子伴侣，选择性结合非天然蛋白质， 促进它们的折叠或降解，已经显示出调节聚集和毒性 在神经退行性疾病模型中。最近，Frydman发现， 伴侣蛋白TRiC/CCT在体内控制多聚谷氨酰胺聚集和毒性， 有效的聚集抑制剂。引人注目的是，我们发现TRiC亚基CCT 1等 特别是140个氨基酸的CCT 1顶端结构域，直接抑制聚集， 与亨廷顿病的病原体有关的神经毒性？S病（多聚谷氨酰胺- 扩展的亨廷顿蛋白外显子1）。 我们建议使用cryoEM来研究生长的亨廷顿原纤维的形态 在不同的时间，并看到用TRiC处理后的聚集。