Phase separation of microtubule-binding proteins – implications for neuronal function and disease

ABSTRACT Protein liquid–liquid phase separation (LLPS) is driven by intrinsically disordered regions and multivalent binding domains, both of which are common features of diverse microtubule (MT) regulators. Many in vitro studies have dissected the mechanisms by which MT-binding proteins (MBPs) regulate MT nucleation, stabilization and dynamics, and investigated whether LLPS plays a role in these processes. However, more recent in vivo studies have focused on how MBP LLPS affects biological functions throughout neuronal development. Dysregulation of MBP LLPS can lead to formation of aggregates – an underlying feature in many neurodegenerative diseases – such as the tau neurofibrillary tangles present in Alzheimer's disease. In this Review, we highlight progress towards understanding the regulation of MT dynamics through the lens of phase separation of MBPs and associated cytoskeletal regulators, from both in vitro and in vivo studies. We also discuss how LLPS of MBPs regulates neuronal development and maintains homeostasis in mature neurons.