ROLE OF A MITCHONDRIAL PP2A IN NEURONAL SURVIVAL

描述(申请人提供)：异三聚体蛋白磷酸酶2A(PP2A)是一种主要的丝氨酸/苏氨酸磷酸酶，调节许多细胞信号转导途径。PP2A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，因为其启动子上的CAG重复扩增导致了神经退行性疾病脊髓小脑性共济失调-12。我们实验室最近发表的工作表明，B-beta的剪接变体B-beta2含有一个N端靶向序列，将PP2A定向到线粒体，促进神经细胞系的凋亡。在这里，我建议研究B-β2与线粒体结合并拮抗生存的机制。在三个目标中，我将阐述B-β2通过(1)阻断线粒体输入受体，(2)使线粒体膜外膜的Bcl2家族生存调节因子去磷酸化，以及(3)通过干扰线粒体代谢来促进细胞凋亡的假说。这项提案中的发现将与开发针对B-Beta2的新疗法相关，以防止脑缺血和神经变性期间的细胞凋亡。

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.