Tau Condensates

Many proteins, particularly those that are intrinsically disordered and carry charges have a tendency to undergo liquid liquid phase separation (LLPS). Phase separation is a widespread mechanism by which cells concentrate a set of proteins to perform molecular reactions, and appear to compartmentalize molecular functions. Among the intrinsically disordered proteins are a subset that tend to form solid inclusions in cells and contribute to the pathology of several neurodegenerative diseases. Among this subset is the tau protein, a critically important inclusion in a class of conditions known as the tauopathies, which include Alzheimer’s disease. Tau in neurons strongly and selectively associates with RNA species, most notably tRNA with a nanomolar dissociation constant. Furthermore, tau and RNA, under charge matching conditions, undergo LLPS in a process known as complex coacervation. Tau-RNA LLPS is reversible, and can persist for more than 15 h without subsequent fibrilization, although after longer time periods β-sheet content can be detected by thioflavin T. These findings suggest that LLPS tau droplets or condensates can be placed on a pathway to fibrillization and be arrested by solidification or dissolve into a soluble state, depending on the condition at hand, suggesting a regulatory and physiological role for the phase separated state of tau.