PME-1: Pathogenetic Role and Therapeutic Opportunity in Neurodegenerative Mixed Proteinopathies

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PROJECT SUMMARY Alzheimer’s disease is characterized by plaques formed by amyloid-beta (Ab) and tangles formed by phosphorylated tau, while Parkinson’s disease and dementia with Lewy bodies are characterized by aggregates of phosphorylated a-synuclein (a-Syn). However, aggregates of these proteins co-occur with high frequency in the brains of individuals with neurodegenerative disorders, and this co-occurrence is coincident with more rapid neurodegeneration. This overlap, together with evidence from cell and animal models point to synergistic pathogenic interactions among a-Syn, Ab, and tau that are poorly understood, and identifying novel therapeutically tractable targets for these complex debilitating disorders remains a major unmet medical need. We hypothesize that protein phosphatase 2A (PP2A) plays a central role in mediating these interactions and driving neurodegeneration, and that the demethylating enzyme of this master regulator, PP2A methylesterase, PME-1, is a viable therapeutic target for disease modification. PP2A dephosphorylates disease-associated forms of a-Syn, tau, and amyloid-b precursor protein (APP), and is itself dysregulated by increased levels of reactive oxygen species that are also a feature of diseased brains. In addition, PME-1 levels are increased and PP2A is demethylated and, therefore, hypoactive in brains affected with these diseases. Importantly, inhibiting PME-1 protects mice against individual exposure to pathogenic forms of a-Syn and Ab. Here, we propose to examine the role of PME-1 in the synergistic interactions among these pathogenic proteins as well as the therapeutic potential of inhibiting PME-1. In Aim 1, we will test the behavioral, biochemical, and neuropathological consequences of exposure to combinations of these proteins using novel mouse models with impaired PP2A methylation and activity due to increased PME-1 expression. And in Aim 2, we will test whether PME-1 inhibition, using genetic and pharmacological approaches, protects against the phenotype resulting from exposure to combinations of these pathogenic proteins. The results of these studies will elucidate the mechanisms underlying a-Syn-, Ab-, and tau-related co-pathologies, and test the potential of PME-1 inhibition as a disease modifying therapeutic approach for these disorders.