Liquid-liquid phase separation and conformational strains of α-Synuclein: implications for Parkinson's disease pathogenesis

Parkinson's disease (PD) and other synucleinopathies are characterized by the aggregation and deposition of alpha-synuclein (α-syn) in brain cells, forming insoluble inclusions such as Lewy bodies (LBs) and Lewy neurites (LNs). The aggregation of α-syn is a complex process involving the structural conversion from its native random coil to well-defined secondary structures rich in β-sheets, forming amyloid-like fibrils. Evidence suggests that intermediate species of α-syn aggregates formed during this conversion are responsible for cell death. However, the molecular events involved in α-syn aggregation and its relationship with disease onset and progression remain not fully elucidated. Additionally, the clinical and pathological heterogeneity observed in various synucleinopathies has been highlighted. Liquid-liquid phase separation (LLPS) and condensate formation have been proposed as alternative mechanisms that could underpin α-syn pathology and contribute to the heterogeneity seen in synucleinopathies. This review focuses on the role of the cellular environment in α-syn conformational rearrangement, which may lead to pathology and the existence of different α-syn conformational strains with varying toxicity patterns. The discussion will include cellular stress, abnormal LLPS formation, and the potential role of LLPS in α-syn pathology.