Liquid-liquid phase separation of tau and α-synuclein: A new pathway of overlapping neuropathologies

Liquid-liquid phase separation (LLPS) is a critical phenomenon that leads to the formation of liquid-like membrane-less organelles within cells. Advances in our understanding of condensates reveal their significant roles in biology and highlight how their dysregulation may contribute to disease. Recent evidence indicates that the high protein concentration in coacervates may lead to abnormal protein aggregation associated with several neurodegenerative diseases. The presence of condensates containing multiple amyloidogenic proteins may play a role in the co-deposition and comorbidity seen in neurodegeneration. This review first provides a brief overview of the physicochemical bases and molecular determinants of LLPS. It then summarizes our understanding of Tau and alpha-synuclein (AS) phase separation, key proteins in Alzheimer's and Parkinson's diseases. By integrating recent findings on complex Tau and AS coacervation, this article offers a fresh perspective on how LLPS may contribute to the pathological overlap in neurodegenerative disorders and provide a novel therapeutic target to mitigate or prevent such conditions.