Modulation of biomolecular condensation of alpha-synuclein variants by eprodisate

Aggregation of α-synuclein (α-SYN) into amyloid structures is closely associated with Parkinson’s disease (PD). Prevention of α-SYN aggregation has been validated as a key strategy to manage PD. α-SYN undergoes liquid-liquid phase separation (LLPS) via biomolecular condensation that facilitates nucleation and amyloid formation in liquid droplets. In this work, the effect of eprodisate (a glycosaminoglycan mimetic) on the formation of biomolecular condensates by α-SYN and its pathology-relevant variants has been investigated. Eprodisate affected the formation of α-SYN condensates, increased the fluidity inside droplets and inhibited α-SYN from turning into amyloid. It also attenuated aggregation of α-SYN variants in the presence of chondroitin sulphate. Eprodisate inhibited phase separation, hydrogel formation and amyloid aggregation of PD-related α-SYN A30P, α-SYN S129D and C-terminal truncated variants. It reduced oxidative stress, decreased α-SYN-positive aggregates and increased cell survival. These findings show that eprodisate may be explored further as an ameliorative therapy in PD. Aggregation of α-synuclein through liquid–liquid phase separation contributes to amyloid formation associated with Parkinson’s disease. Here, the authors demonstrate that the glycosaminoglycan mimetic eprodisate modulates α-synuclein condensation, inhibits amyloid aggregation of pathology-relevant variants and reduces cellular toxicity, highlighting its potential as a therapeutic strategy for Parkinson’s disease.