Exploring chaperone code control of TDP-43 function in ALS

探索 ALS 中 TDP-43 功能的伴侣代码控制

• 批准号: 10724923
• 负责人: Andrew William Truman
• 金额: $ 41.38万
• 依托单位: UNIVERSITY OF NORTH CAROLINA CHARLOTTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724923
• 关键词: Amyotrophic Lateral Sclerosis; Binding; Binding Proteins; Biological Process; Biology; Cells; Code; Collection; Communities; Complex; DNA-Binding Proteins; Data; Mammalian Cell; Mass Spectrum Analysis; Modification; Molecular Chaperones; Mutation; Nature; Neurodegenerative Disorders; Phosphorylation; Phosphorylation Site; Post-Translational Protein Processing; Property; Protein C; Protein Family; Protein Isoforms; Proteins; Proteomics; Regulation; Research; Role; Site; Specificity; Structure; Surface; TDP-43 aggregation; Therapeutic; Toxic effect; Work; Yeasts; amyotrophic lateral sclerosis therapy; crosslink; frontotemporal lobar dementia amyotrophic lateral sclerosis; novel; novel therapeutics; prevent; protein TDP-43; protein aggregation; protein folding; response; tool

Aggregation of the TAR DNA-binding protein (TDP-43) is associated with neurodegenerative disorders such as frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS). Any strategy that alters TDP-43 aggregation, function and cellular toxicity may form the basis of potent novel ALS therapies. A major regulator of protein folding and aggregation in cells is the Hsp70 molecular chaperone. Research has primarily focused on how Hsp70 function specificity arises through regulation of a) expression of Hsp70, b) isoform differences in the Hsp70 protein family and c) the variety of co-chaperone proteins that bind to the Hsp70 molecule. Despite the proteomic identification of over seventy phosphorylation sites on both yeast and mammalian Hsp70, the biological function of most of these sites remains unknown. In this proposal, we intend to investigate the connection between post-translational modification (PTM) of Hsp70 and TDP-43 function. In particular, we will determine how chaperone PTMs are altered in response to the presence of TDP-43 in mammalian and yeast cells and how the modification of these PTMs impacts TDP-43 toxicity. Finally, we intend to use cross-linking mass spectrometry to analyze the interaction between Hsp70 and TDP-43 with a focus on the interaction surface between these two proteins. This information will provide ket preliminary data for larger studies that determine the mechanisms regulating these PTMs and their specific effect on TDP-43.

焦油DNA结合蛋白（TDP-43）的聚集与此类神经退行性疾病有关 作为额颞变性（FTD）和肌萎缩性侧面硬化症（ALS）。任何改变TDP-43的策略 聚集，功能和细胞毒性可能构成有效的新型ALS疗法的基础。主要的监管机构 细胞中蛋白质折叠和聚集的是HSP70分子伴侣。研究主要集中 关于HSP70的功能特异性如何通过调节a）hsp70的表达，b）同工型差异 HSP70蛋白家族和c）与HSP70分子结合的多种伴侣蛋白。尽管 酵母和哺乳动物HSP70上超过70个磷酸化位点的蛋白质组学鉴定， 这些站点大多数的生物学功能仍然未知。 在此提案中，我们打算研究翻译后修改（PTM）之间的联系 HSP70和TDP-43功能。特别是，我们将确定伴侣PTM的响应方式如何改变 哺乳动物和酵母细胞中TDP-43的存在以及这些PTM的修饰如何影响TDP-43 毒性。最后，我们打算使用交联的质谱法分析HSP70和 TDP-43专注于这两种蛋白质之间的相互作用表面。此信息将提供KET 较大研究的初步数据，这些数据确定调节这些PTM的机制及其特定效果 在TDP-43上。