Small Molecules Modulate Liquid‐to‐Solid Transitions in Phase‐Separated Tau Condensates

Abstract

AbstractIn Tau protein condensates formed by the Liquid–Liquid Phase Separation (LLPS) process, liquid‐to‐solid transitions lead to the formation of fibrils implicated in Alzheimer's disease. Here, by tracking two contacting Tau‐rich droplets using a simple and nonintrusive video microscopy, we found that the halftime of the liquid‐to‐solid transition in the Tau condensate is affected by the Hofmeister series according to the solvation energy of anions. After dissecting functional groups of physiologically relevant small molecules using a multivariate approach, we found that charged groups facilitate the liquid‐to‐solid transition in a manner similar to the Hofmeister effect, whereas hydrophobic alkyl chains and aromatic rings inhibit the transition. Our results not only elucidate the driving force of the liquid‐to‐solid transition in Tau condensates, but also provide guidelines to design small molecules to modulate this important transition for many biological functions for the first time.