Liquid-Liquid Phase Separation and Its Mechanistic Role in Pathological Protein Aggregation

Liquid-liquid phase separation (LLPS) of proteins underlies the formation of membrane-less organelles. While it has been recognized for some time that these organelles are of key importance for normal cellular functions, a growing number of recent observations indicate that LLPS may also play a role in disease. In particular, numerous proteins that form toxic aggregates in neurodegenerative diseases, such as amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and Alzheimer's disease, were found to be highly prone to phase separation, suggesting that there might be a strong link between LLPS and the pathogenic process in these disorders. This review aims to assess the molecular basis of this link through exploration of the intermolecular interactions that underlie LLPS and aggregation and the underlying mechanisms facilitating maturation of liquid droplets into more stable assemblies, including so-called labile fibrils, hydrogels, and pathological amyloids. Recent insights into the structural basis of labile fibrils and potential mechanisms by which these relatively unstable structures could transition into more stable pathogenic amyloids are also discussed. Finally, this review explores how the environment of liquid droplets could modulate protein aggregation by altering kinetics of protein self-association, affecting folding of protein monomers, or changing aggregation pathways.