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

Abstract

In Tau protein condensates formed by the Liquid-Liquid Phase Separation (LLPS) process, liquidto-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.

Chemical tools for study and modulation of biomolecular phase transitions

“…In one of the few systematic studies of its kind, Jonchhe et al found that hydrophobic moieties in small molecules delay the onset of a liquid-to-solid phase transition in tau LLPS droplets. 151 In the same work, TMAO is shown to be an especially potent inhibitor of the liquid-to-solid transition, which is consistent with the observation that amphiphilic compounds like bis-ANS and ATP can drive LLPS.…”

Fluorogenic methodology for visualization of phase separation in chemical biology

“…2b). Using a simple and non-invasive video microscope to track two touching tau-rich droplets, Jonchhe 17 et al observed that liquid eventually turned solid in the LLPS condensate (Fig. 2c).…”

Intracellular Liquid‐Liquid Phase Separation Induces Tunable Anisotropic Nanocrystal Growth for Multidimensional Analysis

“…in cells condense into independent droplets of different sizes from weak interactions, dense phase is formed, phase separation occurs and coexists with light phase. [25][26][27] LLPS is a critical process in living organisms and it is isolated from its surroundings and is considered a microenvironment for the biomineralization of minerals. [28,29] The amorphous calcium carbonates (ACC) nucleate and crystallize in droplets.…”