ROLE OF A MITCHONDRIAL PP2A IN NEURONAL SURVIVAL

描述（由申请人提供）：异源三聚体蛋白磷酸酶2A（PP 2A）是一种主要的Ser/Thr磷酸酶，可调节许多细胞信号转导途径。PP 2A的神经元特异性B-β调节亚基似乎是一个关键的生存调节因子，因为其启动子中的CAG重复扩增是神经退行性疾病脊髓小脑共济失调12型的原因。我们实验室最近发表的工作表明，B-β 2，B-β的剪接变体，含有N-末端靶向序列，将PP 2A导向线粒体，以促进神经元细胞系的凋亡。在这里，我建议调查的机制，B-β 2结合线粒体和拮抗生存。在三个目标中，我将讨论B-β 2通过（1）阻断线粒体输入受体，（2）在线粒体外膜脱磷酸化Bcl-2家族生存调节因子，和（3）干扰线粒体代谢促进细胞凋亡的假设。该提案中的发现将与靶向B-beta2以防止脑缺血和神经变性期间细胞凋亡的新疗法的开发相关。

DESCRIPTION (provided by applicant): Heterotrimeric protein phosphatase 2A (PP2A) is a major Ser/Thr phosphatase that regulates many cellular signal transduction pathways. The neuron-specific B-beta regulatory subunit of PP2A appears to be a critical survival regulator, since a CAG repeat expansion in its promoter is responsible for the neurodegenerative disorder spinocerebellar ataxia type-12. Recently published work from our laboratory has demonstrated that B-beta2, a splice variant of B-beta, contains a N-terminal targeting sequences that directs PP2A to mitochondria to promote apoptosis in a neuronal cell line. Here, I propose to investigate the mechanism by which B-beta2 binds to mitochondria and antagonizes survival. In three aims, I will address the hypotheses that B-beta2 promotes apoptosis by (1) blocking the mitochondrial import receptor, (2) dephosphorylating Bcl-2 family survival regulators at the outer mitochondrial membrane, and by (3) interfering with mitochondrial metabolism. The findings in this proposal will be relevant for the development of novel therapies that target B-beta2 to prevent apoptosis during brain ischemia and neurodegeneration.