Recruitment of Aβ into α-Synuclein Condensates Catalyzes Primary Nucleation of α-Synuclein Aggregation

Abstract

The aggregation of amyloid-β (Aβ) and α-synuclein (αSyn) is linked to Alzheimer’s and Parkinson’s diseases, with growing evidence suggesting possible interactions between Aβ and αSyn in the pathology of these neurodegenerative conditions. In this context, the recent observation that protein aggregation into amyloid fibrils may take place within liquid condensates generated through liquid–liquid phase separation prompts the question of how amyloidogenic proteins interact with each other, and more specifically whether Aβ can influence the overall phase behavior of αSyn or vice versa. To address this question, we investigated the interplay between Aβ40, the most abundant form of Aβ, with αSyn. We found that monomeric Aβ40 is sequestered into αSyn condensates, where it enhances heterogeneous primary nucleation, and accelerates the aggregation of αSyn within the liquid condensates. Using a chemical kinetics framework, we further showed that this liquid-to-solid transition is not significantly affected by adding preformed Aβ40 fibrillar seeds, further indicating that monomeric Aβ40 specifically enhances the primary nucleation of αSyn within the condensed phase. These findings identify some of the key mechanistic processes underlying amyloid aggregation within liquid condensates, prompting further investigations into the possible role of Aβ and αSyn cocondensation interactions in the onset and progression of neurodegenerative disorders.

This study reports the effect of amyloid-β (Aβ) on the phase transitions of α-synuclein (αSyn), showing that Aβ40 is recruited into αSyn condensates where it accelerates αSyn amyloid aggregation.