Liquid - liquid phase separation of tau: Driving forces, regulation, and biological implications

The past 15 years have witnessed an explosion in the studies of biomolecular condensates that are implicated in numerous biological processes and play vital roles in human health and diseases. Recent findings demonstrate that the microtubule-associated protein tau forms liquid condensates through liquid-liquid phase separation (LLPS) in in vitro experiments using purified recombinant proteins and cell-based experiments. Although in vivo studies are lacking, liquid condensates have emerged as an important assembly state of physiological and pathological tau and LLPS can regulate the function of microtubules, mediate stress granule formation, and accelerate tau amyloid aggregation. In this review, we summarize recent advances in tau LLPS, aiming to unveiling the delicate interactions driving tau LLPS. We further discuss the association of tau LLPS with physiology and disease in the context of the sophisticated regulation of tau LLPS. Deciphering the mechanisms underlying tau LLPS and the liquid-to-solid transition enables rational design of molecules that inhibit or delay the formation of tau solid species, thus providing novel targeted therapeutic strategies for tauopathies.