Liquid-Liquid Phase Separation of Tau Protein in Neurobiology and Pathology

Tau is an intrinsically unfolded protein that, aside from its important role in the regulation of microtubule stability, harbors an emerging number of other functions. In order to find explanations for some longtime unsolved aspects of neuronal tau biology in the brain, we may have to step aside from observing tau molecules in dilute solutions, and from assuming a mono-molecular physicochemical behavior of molecules in the cell. Liquid condensed phases of tau proteins, which form through the biophysical process of liquid-liquid phase separation (LLPS), behave like liquids and thereby offer a new regime of interactions in the cell. So far, there is evidence that tau condensates (i) play a role for neurodegenerative diseases by transitioning into aggregated forms of tau, (ii) are involved in microtubule binding, nucleation, and bundling, and (iii) are interacting with RNA molecules, which could impact RNA homeostasis and transcription. Likewise the functions of monomeric tau, also tau condensation is regulated by post-translational modifications and can be influenced by the local environment, for example in neuronal sub-compartments. However, we are just beginning to understand the physicochemistry of tau LLPS, and the biological role of tau condensation has to be explored in the next years.