The N-terminal Region of α-Synuclein Controls Amyloid Nucleation at the Condensate Interface

Abstract

Abstractα-Synuclein can self-assemble into amyloid fibrils in neurodegenerative diseases, including Parkinson’s disease. Recent studies show α-synuclein can also undergo liquid-liquid phase separation, forming biomolecular condensates. The interconnection between α-synuclein amyloid formation and liquid-liquid phase separation is evident as these condensates can mature into solid gel-like condensates containing amyloid fibrils. Furthermore, N-terminally truncated α-synuclein fragments have been found in aggregates isolated from Parkinson’s disease affected brains and are known to affectin vitroaggregation.Here, we show that physiologically relevant N-terminal truncation of residues 1-4 significantly enhances α-synuclein self-assembly. Combining amyloid aggregation and liquid-liquid phase separation studies, we determined that this truncation increases the surface-dependent aggregation of α-synuclein, specifically at the fibril and lipid-vesicle surface, and the condensate interface. Our results enhance the understanding of α-synuclein pathology, offering new targets for therapeutic treatment. Furthermore, our quantitative approach can be extended to other systems to broaden the understanding of liquid-liquid phase separation in biology.