Modulation of biomolecular condensation of alpha-synuclein variants by eprodisate.
The study demonstrates that eprodisate, a glycosaminoglycan mimetic, disrupts α‑synuclein liquid–liquid phase separation, increases droplet fluidity, inhibits hydrogel and amyloid formation of several PD-relevant α‑syn variants, reduces oxidative stress and α‑syn–positive aggregates, and improves…
What the AI sees
The study demonstrates that eprodisate, a glycosaminoglycan mimetic, disrupts α‑synuclein liquid–liquid phase separation, increases droplet fluidity, inhibits hydrogel and amyloid formation of several PD-relevant α‑syn variants, reduces oxidative stress and α‑syn–positive aggregates, and improves…
Research significance
This identifies a repurposing-ready compound that targets a mechanistically novel, upstream process (biomolecular condensation/LLPS) to prevent α‑syn aggregation, giving a tangible translational lead for PD therapy development pending in vivo efficacy and safety studies.
Source abstract
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.