Cell Signaling and Neurodegeneration

细胞信号传导和神经变性

• 批准号: 8245795
• 负责人: Harry T. Orr
• 金额: $ 39.33万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245795
• 关键词: Address; Affect; Alternative Splicing; Biological; Biology; Cell Nucleus; Cerebellar degeneration; Complex; Coupling; Deposition; Disease; Generations; Glutamine; Goals; Health; Lead; Length; Lysine; Modification; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathway interactions; Peptides; Phosphorylation; Phosphotransferases; Play; Post-Translational Protein Processing; Property; Proteins; Purkinje Cells; RNA Processing; Regulation; Role; Series; Signal Transduction; Site; Testing; Transcription Process; Transgenic Mice; Translations; Type 1 Spinocerebellar Ataxia; Vertebral column; Work; cellular targeting; chemical group; in vivo; mutant; polyglutamine; protein complex; protein function; research study; therapy development

DESCRIPTION (provided by applicant): Spinocerebellar ataxia type 1 (SCA1) is an untreatable fatal autosomal dominant neurodegenerative disorder caused by the expansion of a glutamine repeat within the SCA1-encoded protein ATXN1. Previous work has shown that the sub cellular deposition and localization of mutant ATXN1 plays a critical role in the pathogenesis of SCA1. For many proteins, the peptide backbone is often altered by post-translational modifications (PTMs) and covalent attachment of chemical groups that change the properties, and hence the function of proteins. ATXN1 is modified by phosphorylation at two sites, S776 and S239. In addition this protein is sumoylated at a minimum of five lysine residues, one of which is in the AXH domain a region of ATXN1 important for several crucial interactions. Thus the goal of the studies proposed in this application is to elucidate the pathways that lead to the phosphorylation and sumoylation of ATXN1 in vivo. We will assess the extent to which the post-translational modification of ATXN1 impact its biology, in particular the ability of mutant ATXN1 to cause the degeneration of cerebella Purkinje cells. PUBLIC HEALTH RELEVANCE: In undertaking these studies we are focused on testing two hypotheses: 1) Post- translation modifications are important for regulating the normal function of ATXN1 and pathogenesis induced by mutant ATXN1, and 2) As such they are targets for development of treatments for SCA1.

描述（由申请方提供）：脊髓小脑共济失调1型（SCA 1）是一种无法治疗的致死性常染色体显性遗传神经退行性疾病，由SCA 1编码的蛋白ATXN1内谷氨酰胺重复序列扩增引起。先前的工作表明，突变ATXN1的亚细胞沉积和定位在SCA1的发病机制中起着关键作用。对于许多蛋白质，肽骨架通常通过翻译后修饰（PTM）和化学基团的共价连接而改变，所述化学基团改变蛋白质的性质并因此改变蛋白质的功能。ATXN1通过在两个位点S776和S239磷酸化修饰。此外，该蛋白质在至少5个赖氨酸残基处被sumoylated，其中一个在AXH结构域中，该结构域是ATXN1的几个关键相互作用的重要区域。因此，在本申请中提出的研究的目标是阐明导致ATXN1在体内磷酸化和类小泛素化的途径。我们将评估ATXN1的翻译后修饰对其生物学的影响程度，特别是突变ATXN1引起小脑浦肯野细胞变性的能力。公共卫生相关性：在进行这些研究时，我们集中于测试两个假设：1）翻译后修饰对于调节ATXN1的正常功能和突变体ATXN1诱导的发病机制是重要的，和2）因此它们是开发SCA1治疗的靶标。