Redox regulation of protein functions linked to neurodegeneration

与神经变性相关的蛋白质功能的氧化还原调节

• 批准号: 10267703
• 负责人: Benjamin P Tu
• 金额: $ 35.88万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-25 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10267703
• 关键词: Affect; Amyotrophic Lateral Sclerosis; Antibodies; Antisense Oligonucleotides; Autophagocytosis; Binding Proteins; Biochemical; Biological Assay; Biological Markers; Biology; Brain; Cell Death; Cell Line; Cell physiology; Cells; Coupled; Development; Glean; Growth; Health; Human; Hydrogen Peroxide; Individual; Knowledge; Lead; Link; Mammalian Cell; Mass Spectrum Analysis; Mediating; Metabolic; Metabolism; Methionine; Methods; Mitochondria; Molecular; Motor Neurons; Mus; Mutate; Mutation; Mutation Analysis; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Orthologous Gene; Output; Oxidation-Reduction; Oxidative Stress; Oxides; Pathology; Phase; Phenotype; Protein Engineering; Protein Footprinting; Proteins; RNA; RNA Recognition Motif; RNA-Binding Proteins; Regulation; Reporter; Respiration; SCA2 protein; Signal Transduction; Spinocerebellar Ataxias; Stress; Therapeutic; Tissue Sample; Variant; Water; Yeasts; experimental study; improved; innovation; insight; interest; metabolomics; mitochondrial dysfunction; mutant; novel; overexpression; oxidation; polyglutamine; protein TDP-43; protein function; recruit; respiratory; response; sensor; stress granule; therapeutic target; treatment strategy

Project Summary/Abstract: The molecular and metabolic mechanisms that go awry during the course of neurodegeneration remain poorly understood. A conserved protein called ataxin-2 has been linked to neurodegeneration due to the occurrence of polyglutamine tract expansions that can influence the aggregation of itself and other proteins. However, the normal functions of this protein and the consequences of their alteration have not been clear. It was recently shown that the protein can function as a redox sensor to then regulate cellular metabolism and signaling in a manner that sustains mitochondrial health and cell survivability. This proposal will investigate aspects of the mechanism of redox sensing by ataxin-2 in both yeast and mammalian cells, the downstream outputs, as well as the consequences of mutations and variants on associated cellular functions.

项目概要/摘要： 在神经退行性变过程中出错的分子和代谢机制 仍然知之甚少。一种叫做ataxin-2的保守蛋白质与 由于多聚谷氨酰胺束扩张的发生， 自身和其他蛋白质的聚集。然而，这种蛋白质的正常功能和 其改变的后果尚不清楚。最近的研究表明， 可以作为氧化还原传感器来调节细胞代谢和信号传导， 维持线粒体的健康和细胞的存活能力。该提案将调查以下方面： 在酵母和哺乳动物细胞中，共济失调蛋白2的氧化还原敏感机制， 下游输出，以及突变和变异对相关的 细胞功能。