Project Summary Alzheimer’s disease is polygenic, yet the molecular functions and contributions to disease progression of many genetic factors are not understood. Mob4 is a gene whose expression is significantly downregulated in Alzheimer’s disease and whose function is yet to be determined. The goal of this research proposal is to understand the molecular functions of Mob4 in neurons. Previous studies have shown that Mob4 is a core- component of the STRIPAK complex, which contains kinases and the phosphatase PP2A. Mob4 contains a conserved phospho-binding motif that in other Mob family proteins binds phosphorylated kinases. Our preliminary studies show that the conserved phospho-binding motif is required for Mob4 function in neurons. We propose that Mob4 functions, through its phospho-binding motif, to recruit a kinase into the STRIPAK complex for PP2A-mediated dephosphorylation and a reduction in kinase activity. Aim 1 will address if the phospho-binding motif of Mob4 is required for regulation of axonal transport and for long-term memory formation, two neuronal processes that are disrupted in Alzheimer’s disease. Preliminary genetic interaction studies suggest that Tao kinase activity is regulated by Mob4. Previous studies show that Tao kinase can phosphorylate the microtubule associated protein Tau at phospho-sites associated with neurofibrillary tangle formation in Alzheimer’s disease. Aim 2 will determine if Mob4 binds and regulates phospho-Tao kinase activity and identify novel kinases that interact with Mob4. Our studies will provide new insights into the mechanism of Mob4 functions and advance our understanding of how Mob4 dysfunction contributes to Alzheimer’s disease.