Tau liquid–liquid phase separation in neurodegenerative diseases

Tau alone or in the presence of RNA has a high propensity to undergo liquid–liquid phase separation (LLPS), forming liquid droplets. LLPS of full-length tau under physiologically relevant buffer conditions is largely driven by intermolecular electrostatic interactions between oppositely charged protein regions or between tau and RNA. Phosphorylation and other post-translational modifications appear to play a regulatory role in tau LLPS. LLPS has a major impact on tau aggregation into amyloid fibrils. It also leads to unique regulatory mechanisms of fibrillation when multiple tau isoforms are present within the condensates. Tau can undergo LLPS in neurons and this may contribute to normal biological functions of the protein as well as to tau pathology in neurodegenerative diseases. Aggregation of the microtubule-associated protein tau plays a major role in Alzheimer’s disease and several other neurodegenerative disorders. An exciting recent development is the finding that, akin to some other proteins associated with neurodegenerative disease, tau has a high propensity to condensate via the mechanism of liquid–liquid phase separation (LLPS). Here, we discuss the evidence for tau LLPS in vitro, the molecular mechanisms of this reaction, and the role of post-translational modifications and pathogenic mutations in tau phase separation. We also discuss recent studies on tau LLPS in cells and the insights these studies provide regarding the link between LLPS and neurodegeneration in tauopathies. Aggregation of the microtubule-associated protein tau plays a major role in Alzheimer’s disease and several other neurodegenerative disorders. An exciting recent development is the finding that, akin to some other proteins associated with neurodegenerative disease, tau has a high propensity to condensate via the mechanism of liquid–liquid phase separation (LLPS). Here, we discuss the evidence for tau LLPS in vitro, the molecular mechanisms of this reaction, and the role of post-translational modifications and pathogenic mutations in tau phase separation. We also discuss recent studies on tau LLPS in cells and the insights these studies provide regarding the link between LLPS and neurodegeneration in tauopathies. a heterotypic LLPS of protein/RNA mixtures driven by attractive electrostatic interactions between protein’s positively charged Arg/Lys residues and negatively charged phosphate groups of RNA. polymers such as dextran or polyethylene glycol that are used to increase the effective protein concentration and, therefore, mimic the conditions of the macromolecules in the crowded cytoplasm. demixing of a two or multiple component system (e.g., several proteins, protein–RNA mixture). demixing of a single component system. concentration of a given macromolecule at which it starts to undergo demixing into condensed and dilute phases. an aliphatic alcohol that disrupts hydrophobic interactions. It is commonly used to probe the nature of interactions within liquid-like condensates.