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.

TAR dna结合蛋白（TDP-43）的聚集与神经退行性疾病有关