Oligomeric assemblies of the protein α-synuclein are believed to be responsible for the neurodegeneration of Parkinson’s disease and related synucleinopathies. Little is known about the structures of the α-synuclein oligomers due to their transience and heterogeneity. The absence of high-resolution structures of oligomers formed by α-synuclein impedes understanding the synucleinopathies at the molecular level. Here we report the first X-ray crystallographic structure of oligomers of peptides derived from α-synuclein. This structure reveals a hierarchical assembly of β-hairpins. Three β-hairpins assemble to form a triangular trimer. Three copies of the triangular trimer further assemble into basket-shaped nonamers and related octadecamers. These oligomers are cytotoxic against human neuroblastoma cells; further, their cytotoxicity appears to result from aberrant interactions with the cell membrane, thus mimicking the mechanism of action of oligomers formed by the full-length protein. The X-ray crystallographic structure presented here may represent the general motif of oligomers formed by full-length α-synuclein and may allow the rational development of diagnostics and therapeutics for Parkinson’s disease.

X-ray crystallographic structure of oligomers formed by a toxic β-hairpin derived from α-synuclein: Trimers and higher-order oligomers

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.