Phase Separation of Parkinson's Disease Protein α‐Synuclein: Mechanistic Insights but Biological Uncertainties

Assembly of the protein α‐synuclein into ordered cross‐β amyloid fibrils is the key hallmark of Parkinson's disease. The molecular processes involved in the transition of functional α‐synuclein monomers to pathological amyloids remain unclear. Liquid–liquid phase separation has emerged as a possible mechanism for early α‐synuclein assembly. In vitro studies at specific conditions demonstrate phase separation of α‐synuclein into liquid‐like condensates that eventually convert to amyloid‐like aggregates. This review summarizes the current understanding of α‐synuclein phase separation, focusing on the influence of intrinsic protein features, such as disease‐linked mutations, post‐translational modifications, and truncations, as well as external factors, such as metal ions, small molecules, lipid membranes, and interactions with other aggregation‐prone proteins. We also discuss protein conformation changes and mesoscale material property alterations occurring during α‐synuclein condensate formation and maturation. Finally, existing cell‐based studies that assess α‐synuclein phase separation in living systems are described. Taken together, we conclude that further research is required to pinpoint the biological significance of α‐synuclein liquid–liquid phase separation and its putative role in Parkinson's disease progression.