Cell Signaling and Neurodegeneration

细胞信号传导和神经变性

• 批准号: 7056144
• 负责人: Harry T. Orr
• 金额: $ 42.6万
• 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 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7056144
• 关键词: biological signal transduction; cerebellar Purkinje cell; cerebellar ataxia /dyskinesia; enzyme mechanism; enzyme substrate; gene mutation; genetically modified animals; glutamine; laboratory mouse; nerve /myelin protein; neural degeneration; phosphorylation; protein localization; protein structure function; serine threonine protein kinase

DESCRIPTION (provided by applicant): Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by the expansion of a glutamine repeat within the SCA1-encoded protein ataxin-1. Previous work has shown that the subcellular deposition and localization of mutant ataxin-1 plays a critical role in the pathogenesis of SCA1. A key player in numerous cell-signaling pathways, many associated with neurodegeneration, is the enzyme glycogen synthase kinase 3 (GSK3). Our results indicate that serines 776 and 780 of ataxin-1 play a role in the subcellular localization of this protein, perhaps via their phosphorylation by GSK3b. Thus, the goal of the research described below is to determine whether cell-signaling pathways acting through these serines of ataxin-1 are biologically relevant GSK3b has recently emerged as a key target in drug discovery. If it proves to be the case that SCA1 pathogenesis is associated with increased levels of GSK3b activity, GSK3b inhibitors might have a therapeutic role in SCA1.

描述（由申请方提供）：脊髓小脑共济失调1型（SCA 1）是一种常染色体显性遗传神经退行性疾病，由SCA 1编码的蛋白共济失调蛋白-1内谷氨酰胺重复序列扩增引起。先前的研究表明，突变型ataxin-1的亚细胞沉积和定位在SCA 1的发病机制中起着至关重要的作用。糖原合成酶激酶3（GSK 3）是许多细胞信号传导途径中的一个关键参与者，其中许多与神经变性有关。我们的研究结果表明，ataxin-1的丝氨酸776和780在这种蛋白质的亚细胞定位中发挥作用，可能是通过它们被GSK 3b磷酸化。因此，下面描述的研究的目标是确定通过这些共济失调蛋白-1丝氨酸起作用的细胞信号传导途径是否与生物学相关，GSK 3b最近已成为药物发现的关键靶点。如果证实SCA 1发病机制与GSK 3b活性水平升高相关，则GSK 3b抑制剂可能在SCA 1中具有治疗作用。