Rational Modulation of Liquid–Liquid Phase Separation Offers Novel Ways to Combat Tauopathies

The microtubule-associated protein tau plays an essential role in regulating the dynamic assembly of microtubules and is implicated in axonal elongation and maturation, axonal transport, synaptic plasticity regulation, and genetic stability maintenance. Nevertheless, the assembly of tau into neurofibrillary tangles in neurons is a pathological hallmark of a group of neurodegenerative diseases known as tauopathies. Despite enormous efforts and rapid advancements in the field, effective treatment remains lacking for these diseases. In this review, we provide an overview of the structure and phase transition of tau protein. In particular, we focus on the involvement of liquid–liquid phase separation in the biology and pathology of tau. We then discuss several potential strategies for combating tauopathies in the context of phase separation: (i) modulating the formation of tau condensates, (ii) delaying the liquid-to-solid transition of tau condensates, (iii) reducing the enrichment of aggregation-prone species into tau condensates, and (iv) suppressing abnormal post-translational modifications on tau inside condensates. Deciphering the structure–activity relationship of tau phase transition modulators and uncovering the conformational changes in tau during phase transitions will aid in developing therapeutic agents targeting tau in the context of phase separation.