Oleuropein derivatives from olive fruit extracts reduce {alpha}-synuclein fibrillation and oligomer toxicity [Protein Structure and Folding] (Journal of Biological Chemistry)

Aggregation of ?-synuclein (?SN) is implicated in neuronal degeneration in Parkinson`s disease and has prompted searches for natural compounds inhibiting ?SN aggregation and reducing its tendency to form toxic oligomers. Oil from the olive tree (Olea europaea L.) represents the main source of fat in the Mediterranean diet and contains variable levels of phenolic compounds, many structurally related to the compound oleuropein. Here, using ?SN aggregation, fibrillation, size-exclusion chromatography-multiangle light scattering (SEC-MALS)-based assays, and toxicity assays, we systematically screened the fruit extracts of 15 different olive varieties to identify compounds that can inhibit ?SN aggregation and oligomer toxicity and also have antioxidant activity. Polyphenol composition differed markedly among varieties. The variety with the most effective antioxidant and aggregation activities, Koroneiki, combined strong inhibition of ?SN fibril nucleation and elongation with strong disaggregation activity on preformed fibrils and prevented the formation of toxic ?SN oligomers. Fractionation of the Koroneiki extract identified oleuropein aglycone, hydroxyl oleuropein aglycone, and oleuropein as key compounds responsible for the differences in inhibition across the extracts. These phenolic compounds inhibited ?SN amyloidogenesis by directing ?SN monomers into small ?SN oligomers with lower toxicity, thereby suppressing the subsequent fibril growth phase. Our results highlight the molecular consequences of differences in the level of effective phenolic compounds in different olive varieties, insights that have implications for long-term human health.