1) Outer mitochondrial PP2A and PKA in neuronal survival and synapse formation. The balance of mitochondria-associated kinase (PKA/AKAP1) and phosphatase (PP2A/Bβ2) activities regulates apoptosis and other aspects of mitochondrial function. Using gene modified mice and primary hippocampal cultures, we are characterizing the interplay between these outer mitochondrial PP2A and PKA holoenzymes in ischemic and excitotoxic injury, as well as in mitochondrial transport and synapse formation.

2) Regulation of the mitochondrial fission/fusion machinery by reversible phosphorylation. Mutations in the large dynamin-related GTPases that restructure mitochondria can cause neurodegenerative diseases and severe birth defects. Because outer mitochondrial PP2A and PKA control neuronal survival through the mitochondrial fission/fusion equilibrium, we are exploring phosphorylation of mitochondria-shaping enzymes as a novel checkpoint in the cell death program.

3) Regulation of catecholamine biosynthesis by PP2A. Tyrosine hydroxylase (TH), the rate limiting enzyme in the synthesis of dopamine and (nor)epinephrine, is dephosphorylated and inactivated by a neuron-specific PP2A holoenzyme containing the B’β subunit. We are exploring the regulation of TH by PP2A/B’β in vitro, in PC12 cells, and in dopaminergic neurons with the eventual goal of developing new Parkinson’s disease therapies.