Cytotoxic Oligomers and Fibrils Trapped in a Gel-like State of α-Synuclein Assemblies

alpha-Synuclein (alpha-Syn) aggregation is associated with Parkinson's disease (PD) pathogenesis. In PD, the role of oligomers versus fibrils in neuronal cell death is debatable, but recent studies suggest oligomers are a proximate neurotoxin. Herein, we show that soluble alpha-Syn monomers undergo a transformation from a solution to a gel state on incubation at high concentration. Detailed characterization of the gel showed the coexistence of monomers, oligomers, and short fibrils. In vitro, the gel was highly cytotoxic to human neuroblastoma cells. The individual constituents of the gel are short-lived species but toxic to the cells. They comprise a structurally heterogeneous population of alpha-helical and beta-sheet-rich oligomers and short fibrils with the cross-beta motif. Given the recent evidence of the gel-like state of the protein associated with neurodegenerative diseases, the gel state of alpha-Syn in this study represents a mechanistic and structural model for the in vivo toxicity of alpha-Syn in PD.