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

• Published in: Journal of molecular biology 2023-01, Vol.435 (1), p.167713, Article 167713
• Main Authors: Mukherjee, Semanti, Sakunthala, Arunima, Gadhe, Laxmikant, Poudyal, Manisha, Sawner, Ajay Singh, Kadu, Pradeep, Maji, Samir K.
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - metabolism; amyloid; Humans; Lewy Bodies - metabolism; Lewy Bodies - pathology; liquid-liquid phase separation; liquid-to-solid phase transition; Parkinson Disease - metabolism; Parkinson’s disease; Protein Aggregation, Pathological - metabolism; α-Synuclein aggregation
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2022.167713

[Display omitted] •The aberrant amyloid aggregation of α-Syn is a key pathological event in PD.•LLPS of α-Syn drives the nucleation for amyloid aggregation and hydrogel formation.•PD-associated factors modulate the kinetics of LLPS and LLPS-mediated aggregation.•Domain-specific interactions regulate the molecular mechanism of α-Syn LLPS.•Heterotypic /multicomponent LLPS of α-Syn might have pathophysiological relevance. Aberrant aggregation of the misfolded presynaptic protein, α-Synuclein (α-Syn) into Lewy body (LB) and Lewy neuritis (LN) is a major pathological hallmark of Parkinson’s disease (PD) and other synucleinopathies. Numerous studies have suggested that prefibrillar and fibrillar species of the misfolded α-Syn aggregates are responsible for cell death in PD pathogenesis. However, the precise molecular events during α-Syn aggregation, especially in the early stages, remain elusive. Emerging evidence has demonstrated that liquid–liquid phase separation (LLPS) of α-Syn occurs in the nucleation step of α-Syn aggregation, which offers an alternate non-canonical aggregation pathway in the crowded microenvironment. The liquid-like α-Syn droplets gradually undergo an irreversible liquid-to-solid phase transition into amyloid-like hydrogel entrapping oligomers and fibrils. This new mechanism of α-Syn LLPS and gel formation might represent the molecular basis of cellular toxicity associated with PD. This review aims to demonstrate the recent development of α-Syn LLPS, the underlying mechanism along with the microscopic events of aberrant phase transition. This review further discusses how several intrinsic and extrinsic factors regulate the thermodynamics and kinetics of α-Syn LLPS and co-LLPS with other proteins, which might explain the pathophysiology of α-Syn in various neurodegenerative diseases.