Abstract Oligomeric species populated during α-synuclein aggregation are considered key drivers of neurodegeneration in Parkinson’s disease. However, their structure and the molecular determinants driving their conversion to fibrils remain elusive. In this work, we determined the symmetry and architecture of α-synuclein oligomers, dissecting the conformational properties of individual chains within these toxic assemblies. We demonstrate that the NAC domain is insufficient to promote oligomer to fibril conversion; instead, this transition is controlled by a short α-synuclein N-terminal motif. A missense mutation causing early-onset Parkinson’s disease remodels this N-terminal region conformation, which results in a population of long-lived oligomers less susceptible to disaggregation by the human Hsp70 machinery. Our results provide a structural understanding of oligomer to amyloid conversion and identify targets for therapeutic intervention. One sentence summary α-Synuclein oligomers are symmetric and well-organized particles with a short N-terminal region controlling fibril conversion.

The structural architecture of an α-synuclein toxic oligomer