Neuronal interactome changes upon aggregation of Tau

To understand at molecular level how aggregation of Tau modulates its interactions with proteins we reveal key determinant for derailing Tau protein network. By performing quantitative AP-MS we define a new set of interactors which bind Tau upon fibril formation. These interactors contain disordered regions with a unique amino acidic footprint. Such regions are enriched in positively charged Arginines which can engage aberrant binding to Tau fibrils through their guanidinium group via pi-stacking. We also find that the Hsp90 chaperone stalls formation of Tau fibrils and reshapes their abnormal interactome.