Liquid-liquid Phase Separation of a-Synuclein: A New Mechanistic Insight for a-Synuclein Aggregation Associated with Parkinson's Disease Pathogenesis

Aberrant aggregation of the misfolded presynaptic protein, cr-Synuclein (cr-Syn) into Lewy body (LB) and Lewy neuritis (LN) is a major pathological hallmark of Parkinson's disease (PD) and other synucle-inopathies. Numerous studies have suggested that prefibrillar and fibrillar species of the misfolded cr-Syn aggregates are responsible for cell death in PD pathogenesis. However, the precise molecular events during cr-Syn aggregation, especially in the early stages, remain elusive. Emerging evidence has demon-strated that liquid-liquid phase separation (LLPS) of cr-Syn occurs in the nucleation step of cr-Syn aggre-gation, which offers an alternate non-canonical aggregation pathway in the crowded microenvironment. The liquid-like cr-Syn droplets gradually undergo an irreversible liquid-to-solid phase transition into amyloid-like hydrogel entrapping oligomers and fibrils. This new mechanism of cr-Syn LLPS and gel for-mation might represent the molecular basis of cellular toxicity associated with PD. This review aims to demonstrate the recent development of cr-Syn LLPS, the underlying mechanism along with the micro-scopic events of aberrant phase transition. This review further discusses how several intrinsic and extrin-sic factors regulate the thermodynamics and kinetics of cr-Syn LLPS and co-LLPS with other proteins, which might explain the pathophysiology of cr-Syn in various neurodegenerative diseases.(c) 2022 Elsevier Ltd. All rights reserved.