Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies

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. Here we identify 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 obilization, and neurodegeneration. We further report a significant increase in transcripts of the endogenous retrovirus class of transposable elements 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. For standard RNA-seq, three independent biological replicates of tau transgenic Drosophila samples were sequenced. Each sample consists of 500 ng of total RNA from six pooled heads (18 heads total). For small RNA-seq, four independent biological replicates were sequenced. The number of control samples is equal to the number of tau transgenic samples. The reads that are available in GSE115606 were extracted using sortmerna where FlyBase release 6.12 was used as the reference for transposable elements and piRNABank was used as the reference for piRNAs.