Curcumin Interacts with α-Synuclein Condensates To Inhibit Amyloid Aggregation under Phase Separation

Area of Science:

• Biochemistry
• Neuroscience
• Pharmacology

Background:

• Alpha-synuclein (α-Syn) amyloid aggregation is a hallmark of Parkinson's disease (PD).
• Recent research indicates that α-Syn undergoes liquid-liquid phase separation (LLPS), which accelerates amyloid formation.
• Targeting α-Syn phase separation presents a novel therapeutic avenue for PD.

Purpose of the Study:

• To investigate the effect of curcumin on α-Syn phase separation and subsequent amyloid aggregation.
• To explore curcumin's potential as a modulator of α-Syn aggregation relevant to Parkinson's disease.

Main Methods:

• Investigated curcumin's interaction with α-Syn during phase separation.
• Assessed the impact of curcumin on α-Syn condensate formation, fluidity, and amyloid conversion.
• Examined curcumin's effects on PD-associated α-Syn mutants (E46K, H50Q) and preformed aggregates.

Main Results:

• Curcumin did not alter α-Syn condensate formation or initial morphology.
• Curcumin significantly decreased the fluidity of α-Syn within condensates.
• Curcumin effectively inhibited α-Syn amyloid formation, including PD mutants, and destabilized preformed aggregates.

Conclusions:

• Curcumin modulates α-Syn amyloid formation by altering protein fluidity during phase separation.
• Small molecules like curcumin can regulate α-Syn amyloid aggregation, offering potential therapeutic strategies for Parkinson's disease.