Increased G3BP2-Tau interaction in Tauopathies is a natural defense against Tau aggregation
Many RNA-binding proteins (RBPs), particularly those associated with RNA granules, promote pathological protein aggregation in neurodegenerative diseases. Here, we demonstrate that G3BP2, a core component of stress granules, directly interacts with Tau and inhibits Tau aggregation. In the human brain, the interaction of G3BP2 and Tau is dramatically increased in multiple Tauopathies and precedes neurofibrillary tangle (NFT) formation in Alzheimer's disease (AD). Surprisingly, Tau pathology is significantly elevated upon loss of G3BP2 in human neurons and brain organoids. Moreover, we find that G3BP2 masks the microtubule-binding region (MTBR) of Tau, thereby inhibiting Tau aggregation. Our study defines a novel role for RBPs as a line of defense against Tau aggregation in Tauopathies. Overall design: Comparative gene expression profiling analysis of RNA-seq data for hiPSC-derived glutamatergic neurons  (FujiFilm Cellular Dynamics; Cat.R1034) after treatment with G3BP2 siRNA (Horizon, Cat. E-015329-00) or NT siRNA (Horizon, Cat. D-001910-10).