Surface wetting is a key determinant of α-synuclein condensate maturation

Abstract

α-Synuclein condensates can mature into amyloid fibrils, demonstrating a link between phase separation and amyloid aggregation. However, the mechanisms driving this maturation are not fully understood, particularly in the context of pathological post-translational modifications that modulate α-synuclein amyloid aggregation. Although often studied in isolation, condensates appear to interact with surfaces in vitro and in the cell. Notably, the N-terminus of α-synuclein is implicated in membrane binding and may influence condensate-surface interactions. Here, we developed a microscopy-based protocol to investigate how N-terminal truncation affects α-synuclein condensate formation, surface wetting, and maturation. We found that N-terminal truncation enhances condensate wettability and accelerates maturation. Conversely, perturbing condensate-surface interactions reduces condensate wettability and delays maturation. These results suggest that enhanced wettability promotes condensate maturation, likely by increasing condensate surface-to-volume ratios. Our findings reveal distinct mechanistic roles for the N-terminus of α-synuclein and highlight condensate wettability and interfacial dynamics as key modulators of aggregate formation.