Tau‐RNA complexes contribute to the pathogenesis and progression in Alzheimer’s disease and related tauopathies

Abstract

BackgroundRecent in vitro and in vivo data show that Tau‐RNA complexes contribute to neuronal dysfunction. However, whether these complexes appear in human tauopathy brains, and whether they are inherently toxic remains unknown. Clarifying the dynamics of tau‐RNA interactions and its relevance in disease would reveal critical and urgently needed information to determine novel therapeutic targets.MethodHuman Alzheimer’s and age‐matched non‐demented control brains were subjected to enhanced cross‐linking immunoprecipitation (eCLIP) sequencing. Amount of RNA was quantified and sequenced in each group. Cell culture experiments were used to validate eCLIP data.ResultTau associated robustly with RNA, many of which have not been previously reported. Early and late‐stage AD tau‐RNA complexes shifted from coding to non‐coding sequences. The consensus sequences that associated with tau contain numerous splice sites and start codons. RNA‐stabilizing species associated with tau in AD brains. Tau overexpression impaired RNA processing, transport, and translation in vitro.ConclusionTau‐RNA interactions, that have not been previously reported, were identified for the first time in human AD brains, and they reveal novel sequences that could be associated with disease.