Structural and molecular determinants of protein phosphatase 2A in Alzheimer's Disease

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Abstract: Protein phosphorylation is the most frequent and best studied post-translational modification. In general, kinases activate signaling pathways, whereas phosphatases behave as the “off-switch” of those paths. In many human diseases this balance is skewed toward kinase hyperactivation and/or phosphatase suppression. The enhanced activity of hyperphosphorylation is a commonality in many diseases as proliferation (in the case of cancer) in unchecked with phosphatase suppression, leading to rapid cell proliferation and tumor growth. Similarly, in the case of Alzheimer’s Disease, the kinase-to-phosphatase activity ratio is skewed, such that the microtubule tau gains a net increase in phosphorylation. Phosphorylated tau aggregates into fibrils that are the hallmark of Alzheimer’s Disease and other neurological disorders including Parkinson’s Disease. Because kinase activity is commonly increased in many diseases, including cancer and Alzheimer’s Disease, kinase inhibitors have recently been developed as therapeutic approaches. Unfortunately, the redundancy in kinases in regulating signaling pathways, an inability to selectively target unique kinases, and the toxicity associated with this approach, have limited progress in the development of kinase inhibitors and their use in the clinic. Theoretically, a phosphatase activator should have a similar therapeutic potential in correcting the kinase:phosphatase activity in disease states. However, the development of ‘activators’ is generally much more difficult than developing an ‘inhibitor’. Therefore, phosphatases, including those in the PP2A family, has long been seen as ‘undruggable’ targets in the pharmaceutical industry. This paradigm has recently been overcome with new strategies as we, and others, have developed small molecules that stabilize phosphatase complexes to reactivate their activity and to combat disease. In this supplemental proposal, we seek to expand the novel strategy we have successfully developed in reactivating PP2A phosphatases in combating cancer, to an analogous strategy in reactivating PP2A phosphatases to combat Alzheimer’s Disease.