Alpha synuclein (αS) aggregates are the main component of Lewy bodies (LBs) associated with Parkinson's disease (PD). A longstanding question about αS and PD pertains to the autosomal dominant E46K αS mutant, which leads to the early onset of PD and LB dementias. The E46K mutation not only promotes αS aggregation but also stabilizes αS monomers in "closed" conformers, which are compact and aggregation-incompetent. Hence, the mechanism of action of the E46K mutation is currently unclear. Here, we show that αS monomers harboring the E46K mutation exhibit more extensive interactions with fibrils compared to those of WT. Such monomer-fibril interactions are sufficient to allosterically drive transitions of αS monomers from closed to open conformations, enabling αS aggregation. We also show that E46K promotes head-to-tail monomer-monomer interactions in early self-association events. This multipronged mechanism provides a new framework to explain how the E46K mutation and possibly other αS variants trigger early-onset PD.
© 2023 The Authors. Published by American Chemical Society.