Targeted downregulation of insulin signaling restricts human tau pathogenesis by reinstating the aberrant heterochromatin loss and mTOR/4EBP/S6K pathway in Drosophila.

Tauopathies are a group of neurodegenerative diseases characterized by the accumulation of paired helical filaments (PHFs)/or neurofibrillary tangles (NFTs) in neuronal/glial cells. Besides hyperphosphorylation of tau protein, aberrant heterochromatin loss and translation dysfunction have emerged as other important aspects contributing to the disease pathogenesis. We have recently reported that tissue-specific downregulation of insulin signaling or its growth-promoting downstream sub-branch effectively reinstates the tau-mediated overactivated insulin pathway, and restricts pathogenic tau hyperphosphorylation and aggregate formation. We next investigated if the downregulation of the insulin pathway or its growth-promoting downstream sub-branch makes any impact on tau-mediated aberrant heterochromatin loss and translation dysfunction. For the first time, we demonstrate that tissue-specific downregulation of insulin signaling or its growth-promoting branch effectively restricts the pathogenic tau-induced heterochromatin loss. We further report that expression of human tau in Drosophila causes induction of the mTOR/4EBP/S6K pathway and energy disbalance which gets effectively balanced upon downregulation of insulin signaling. Our findings establish an imperative role of insulin signaling in effectively mitigating various aspects of tau etiology in Drosophila ranging from hyperphosphorylation, chromatin relaxation, and translational upsurge. Our findings could be beneficial in establishing novel therapeutic options against tauopathies.