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. [unreadable] [unreadable]