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

Misfolding and aggregation of alpha-synuclein (aS) 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 aS 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 aS (aS1-25) as a template for peptide-based aS aggregation antagonists. We report that aS1-2 5 inhibits lipid-induced aS aggregation in a dose dependent manner. aS1-25 functions by binding to lipids to prevent aS binding, with both aS and peptide requiring lipid for inhibition to occur. These findings present a potential mechanistic route for the treatment or prevention of PD.