Inhibition of alpha-synuclein aggregation by AM17, a synthetic resveratrol derivative

Abstract

Parkinson's disease (PD) is linked to the aberrant self-assembly of the amyloid protein, α-synuclein (αS), where αS monomers aggregate to form oligomers and fibrils. Out of the three conformers, αS oligomers are the major toxic agents in PD, while αS fibrils may work as a reservoir for toxic oligomeric conformers. Thus, compounds that inhibit aggregation of αS monomers and disaggregate αS oligomers and fibrils may serve as therapeutic agents against PD. In this regard, resveratrol and its synthetic derivatives (e.g., AM17, which contains a copper ion-selective ionophoric motif) have previously been examined for their inhibitory effects on aggregation of amyloid proteins, such as the β-amyloid peptide implicated in Alzheimer's disease. In the current study, we employed an array of experimental tools, such as Thioflavin T fluorescence, transmission electron microscopy, immuno-dot blot assays, SDS- and native-PAGE, and circular dichroism, to determine the impact of AM17 and resveratrol on αS aggregation. To the best of our knowledge, we show for the first time that AM17 not only inhibits aggregation of αS monomers but also disaggregates αS oligomers and fibrils, independent of the copper ions. Similar αS aggregation inhibitory effects were observed with resveratrol only in the presence of the copper ion. The present study supports the high promise of applicability of AM17 as an effective amyloid aggregation inhibitor for various conformers and protein sequences.