INVESTIGATING THE ROLE OF TRANSPOSABLE ELEMENT DYSREGULATION AS A DRIVER OF NEUROTOXICITY IN TAUOPATHY
Transposable elements, known colloquially as ?jumping genes,? constitute approximately 45% of the humangenome. Cells utilize epigenetic defenses to limit transposable element jumping, including formation of silencingheterochromatin and generation of piwi-interacting RNAs (piRNAs), small RNAs that facilitate clearance oftransposable element transcripts. Transposable element activation has recently been identified as a keymediator of neuronal death in tauopathies, a group of neurodegenerative disorders that are pathologicallydefined by deposits of tau protein in the brain. Using genetic approaches in Drosophila melanogaster models oftauopathy, a causal relationship was established between pathogenic tau-induced heterochromatindecondensation and piwi/piRNA depletion, active transposable element mobilization, and neurodegeneration.Transposable element activation responds to pharmacological inhibition, as 3TC, an FDA-approved, water-soluble nucleoside analog inhibitor of reverse transcriptase, suppresses transposable element mobilization andneuronal death in tau transgenic Drosophila. Transcripts of the human endogenous retrovirus (HERV) class oftransposable elements, among others, were found to be elevated in postmortem brain tissue from humanAlzheimer?s disease and progressive supranuclear palsy, a ?primary? tauopathy. Taken together, these studiesidentify heterochromatin decondensation, piwi/piRNA depletion and consequent transposable element activationas a novel, conserved, pharmacologically targetable, mechanistic driver of neurodegeneration in tauopathy. Toadvance toward our long-term goal of developing mechanism-based therapies for the treatment of humantauopathies, the core objectives of the current proposal are to 1) Test the hypothesis that transposable elementcauses neuroinflammation in tauopathy, 2) Test the hypothesis that transposable element activation occurs inmouse models of tauopathy, and 3) Test the hypothesis that transposable element activation occurs in neuronsof human tauopathy. To address issues of causality, test hypotheses in brains of aged animals with functionalneuronal networks, and determine relevance to human disease, we combine studies in Drosophila, mousemodels of tauopathy, and postmortem human Alzheimer?s disease brain tissue. Successful completion of thesestudies will set the stage for future development of nucleoside analog reverse transcriptase inhibitors as atauopathy therapeutic.