α-Synuclein Early-Oligomers Regulate Self-Assembly through Nucleation and Liquid-Liquid Phase Separation.

The aggregation and deposition of α-synuclein (α-syn) in Lewy bodies is the prominent pathological hallmark of Parkinson's disease. α-Syn aggregation proceeds via liquid-liquid phase separation (LLPS) and liquid-to-solid phase transition (LSPT) within the dense phase, leading to fibril formation. In this study, we reconstituted an instantaneous LLPS system for α-syn, which is primarily governed by electrostatic interactions, uncovering the structure of early-stage oligomers within the dense phase. LLPS promoted the α-syn aggregation process via its intricate nucleation and oligomerization steps, yielding liquid-like droplets composed of hollow spherical oligomers with a loosely packed β-turn conformation. The solidification of dynamic condensates via LSPT, leading to amyloid deposition, may serve as an underlying mechanism for α-syn aberrant aggregation. Our findings deepen the understanding of α-syn self-assembly within the dense phase and provide critical insights into the molecular mechanisms underpinning aggregation kinetics, holding promise for future therapeutic strategies.