蛋白激酶A和磷酸酶2A影响脊髓小脑运动失调症1型的机制

项目名称： 蛋白激酶A和磷酸酶2A影响脊髓小脑运动失调症1型的机制

项目编号： No.31200801

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 神经、认识与心理学

项目作者： 赖少娟

作者单位： 河南工业大学

项目金额： 22万元

中文摘要： 脊髓小脑运动失调症1型是一种遗传性神经退化性疾病，治疗困难，目前尚无特异性治疗。此病由于失调症蛋白1基因突变引起但受别的机制调控。失调症蛋白1丝氨酸776位点的磷酸化直接影响蛋白功能和特性及脊髓小脑运动失调症1型疾病的发生发展。因此如何调控此位点的磷酸化是深入理解疾病发生机理和防治的重要突破口。本项目主要研究调控失调症蛋白1磷酸化的蛋白激酶PKA和磷酸酶PP2A对失调症蛋白1磷酸化的作用机制，蛋白功能和特性的调节，及在脊髓小脑运动失调症1型中所起的作用，以阐明PKA和PP2A与失调症蛋白1及疾病的内在联系，从而揭示失调症蛋白1磷酸化对脊髓小脑运动失调症1型发病的机理和信号传导途径，从新的视觉揭示脊髓小脑运动失调症1型的发生机制，并为脊髓小脑运动失调症1型的防治提供新靶点。

中文关键词： 失调症蛋白1；蛋白激酶A；蛋白磷酸酶2A；磷酸化；SCA1

英文摘要： Spinocerebellar ataxia type 1 (SCA1) is a lethal neurodegenerative disorder caused by expansion of a polyglutamine tract in ATAXIN-1 protein. It is an autosomal dominant inherited disease. Yet, considerable data indicate that ATAXIN-1 residues outside of the glutamine tract have a substantial impact on severity of disease. In SCA1, phosphorylation of ATAXIN-1 at S776 modulates disease and the interaction of ATAXIN-1 with many other proteins. The phosphorylation state of ATAXIN-1 is a dynamic process dictated by both protein kinase A (PKA) and protein phosphatase 2A (PP2A). Due to the importance of ATAXIN-1 phosphorylation at S776, the regulatory mechanism of this site's phosphorylation is critical for understanding the disease pathogenesis and developing avenues for disease therapeutics. The project is focused on the regulation of PKA and PP2A on ATAXIN-1 phosphorylation at S776, ATAXIN-1's function and cellular properties, and focused on PKA and PP2A's roles in SCA1 as well. The results would demonstrate the mechanism of SCA1's pathogenesis in the aspect of phosphorylation regulation and the signaling pathway regulating ATAXIN-1's phosphorylation. The results will also provide some new avenues for SCA1's therapeutics.

英文关键词： ATAXIN-1；PKA；PP2A；phosphorylation；SCA1