The Role of Liquid‒Liquid Phase Separation in the Accumulation of Pathological Proteins: New Perspectives on the Mechanism of Neurodegenerative Diseases

Abstract

It is widely accepted that living organisms form highly dynamic membrane-less organelles (MLOS) with various functions through phase separation, and the indispensable role that phase separation plays in the mechanisms of normal physiological functions and pathogenesis is gradually becoming clearer. Pathological aggregates, regarded as hallmarks of neurodegenerative diseases, have been revealed to be closely related to aberrant phase separation. Specific proteins are assembled into condensates and transform into insoluble inclusions through aberrant phase separation, contributing to the development of diseases. In this review, we present an overview of the progress of phase separation research, involving its biological mechanisms and the status of research in neurodegenerative diseases, focusing on five main disease-specific proteins, tau, TDP-43, FUS, α-Syn and HTT, and how exactly these proteins reside within dynamic liquid-like compartments and thus turn into solid deposits. Further studies will yield new perspectives for understanding the aggregation mechanisms and potential therapeutic strategies, and future research directions are anticipated.