An N-terminal alpha-synuclein fragment binds lipid vesicles to modulate lipid-induced aggregation

Misfolding and aggregation of alpha-synuclein (αS) into toxic conformations is involved in numerous neurodegenerative diseases. In Parkinson’s disease (PD), this occurs within dopaminergic neurons, causing cell death and disease symptoms. During αS aggregation, many protein-protein interactions (PPIs) form over broad and flat protein surfaces, limiting potential for small-molecule intervention. Peptides, however, harbor great therapeutic promise since they can selectively engage with and modulate the large surface areas involved yet are small enough to function as druggable agents if suitably structured. Here, we explore the first 25 residues of αS (αS1–25) as a template for peptide-based αS aggregation antagonists. We report that αS1–25 inhibits lipid-induced αS aggregation in a dose-dependent manner. αS1–25 functions by binding to lipids to prevent αS binding, with both αS and peptide requiring lipid for inhibition to occur. These findings present a potential mechanistic route for the treatment or prevention of PD.