Biomolecular phase separation of microtubule-associated protein tau and its role in the genesis of brain disorders.

Microtubule-associated protein tau (MAP) is a crucial component for cellular cytoskeleton stability. However, upon hyperphosphorylation, these tau proteins detach from microtubules, leading to the genesis of clumpy fibrillar-rich β or paired helical filamental structures known as amyloids. Such deposits predispose a multitude of fatal disorders, including Alzheimer's Disease. The initial event behind such genesis is still a mystery. Today, numerous research studies try to untangle the initial events that lead to the formation of homogeneous and heterogeneous multicomponent plaques in AD, which remain elusive. Since tauopathies are linked to neurodegeneration and the tau tangles damage the neurons and glia, the question of what events trigger the phosphorylation of tau, leading to the molecular crowding of tau repeats, remains largely unknown. Such molecular crowding or initial events before primary nucleation are driven by liquid-liquid phase separation (LLPS), where tau or tau, along with various biomolecules forming dynamic interaction networks leading to the formation of homotypic and heterotypic condensates, ultimately result in co-existing phases before transitioning to nucleation. This review has explored the fundamental principles of LLPS in tau, aiming to establish a link between tau condensates and their pathogenic forms followed by the factors that modulate its phase transition. Our review hopes to provide the scientific community with a strong foundation to build upon, to understand the importance and gravity of studying tau phase separation and the new opportunities it hides within itself.