Divergent effects of pathological α-synuclein truncations and mutations on phase separation

Phase separated condensates of α-synuclein (α-Syn) accelerate amyloid fibril formation, a process implicated in Parkinson's disease pathogenesis. Yet, the precise effects of pathologically relevant α-Syn sequence modifications on this process remain unclear. Here, we show that sequence truncations exert the strongest influence on condensate thermodynamics, material properties, and amyloid aggregation, whereas familial point mutations impart minimal effects. Among the tested familial variants (A30P, H50Q, G51D and A53T), only G51D forms condensates that show a reduced propensity for amyloid fibril formation. Truncated variants undergo rapid gelation and form amyloid fibrils almost immediately. Extending our study to multicomponent systems where α-Syn is a client, we show that α-Syn can dissolve DNA-peptide coacervates or assemble into Pickering clusters on condensate surfaces-regulating condensate fusion and nucleic acid partitioning. These functions depend on the acidic C-terminal domain of α-Syn. Together, our results show disease-relevant modifications can modulate α-Syn phase behavior, both in pathological and physiological contexts.