A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion
Jaime Santos, Jorge Cuéllar, Irantzu Pallarès, Emily J. Byrd, Alons Lends, Fernando Moro, Muhammed Bilal Abdul-Shukkoor, Jordi Pujols, Lorea Velasco‐Carneros, Frank Sobott, Daniel E. Otzen, Antonio N. Calabrese, Arturo Muga, Jan Skov Pedersen, Antoine Loquet, José Valpuesta, Sheena E. Radford, Salvador Ventura
Abstract
Oligomeric species populated during α-synuclein aggregation are considered key drivers of neurodegeneration in Parkinson's disease. However, the development of oligomer-targeting therapeutics is constrained by our limited knowledge of their structure and the molecular determinants driving their conversion to fibrils. Phenol-soluble modulin α3 (PSMα3) is a nanomolar peptide binder of α-synuclein oligomers that inhibits aggregation by blocking oligomer-to-fibril conversion. Here, we investigate the binding of PSMα3 to α-synuclein oligomers to discover the mechanistic basis of this protective activity. We find that PSMα3 selectively targets an α-synuclein N-terminal motif (residues 36-61) that populates a distinct conformation in the mono- and oligomeric states. This α-synuclein region plays a pivotal role in oligomer-to-fibril conversion as its absence renders the central NAC domain insufficient to prompt this structural transition. The hereditary mutation G51D, associated with early onset Parkinson's disease, causes a conformational fluctuation in this region, leading to delayed oligomer-to-fibril conversion and an accumulation of oligomers that are resistant to remodeling by molecular chaperones. Overall, our findings unveil a new targetable region in α-synuclein oligomers, advance our comprehension of oligomer-to-amyloid fibril conversion, and reveal a new facet of α-synuclein pathogenic mutations.