Jump Around, Jump Around: Transposable Element Activation in Tauopathy
Bess Frost Barshop Institute for Longevity and Aging Studies, UT Health Science Center at San Antonio, TX, USA
Transposable elements, known colloquially as “jumping genes,” constitute approximately 45% of the human genome. Cells utilize epigenetic defenses to limit transposable element jumping, including formation of silencing heterochromatin and generation of piwi-interacting RNAs (piRNAs), small RNAs that facilitate clearance of transposable element transcripts. We have identified transposable element activation as a key mediator of neuronal death in tauopathies, a group of neurodegenerative disorders, including Alzheimer's disease, that are pathologically characterized by deposits of tau protein in the brain. Mechanistically, we find that heterochromatin decondensation and reduction of piwi/piRNAs drive transposable element activation in tauopathy. Using genetic and pharmacological approaches in a Drosophila melanogaster model of tauopathy,we provide evidence for a causal relationship between pathogenic tau-induced heterochromatin decondensation, piwi/piRNA depletion, active transposable element mobilization, and neurodegeneration. We find that transcripts of the endogenous retrovirus class of transposable elements are increased in human Alzheimer's disease and progressive supranuclear palsy, suggesting that transposable element dysregulation is conserved in human tauopathy. Taken together, our data identify heterochromatin decondensation, piwi/piRNA depletion and consequent transposable element activation as a novel, pharmacologically targetable, mechanistic driver of neurodegeneration in tauopathy.
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