Curcumin-glucoside, A Novel Synthetic Derivative of Curcumin, Inhibits α-Synuclein Oligomer Formation: Relevance to Parkinson's Disease

Bharathi      Shrikanth Gadad; Parvathy      K. Subramanya; Srinivas      Pullabhatla; Indi      S. Shantharam; Rao      K.S.

doi:10.2174/138161212798919093

Abstract

α-Synuclein aggregation is centrally implicated in Parkinsons disease (PD). It involves multi-step nucleated polymerization process via the formation of dimers, soluble toxic oligomers and insoluble fibrils. In the present study, we synthesized a novel compound viz., Curcumin-glucoside (Curc-gluc), a modified form of curcumin and studied its anti-aggregating potential with α-synuclein. Under aggregating conditions in vitro, Curc-gluc prevents oligomer formation as well as inhibits fibril formation indicating favorable stoichiometry for inhibition. The binding efficacies of Curc-gluc to both α-synuclein monomeric and oligomeric forms were characterized by micro-calorimetry. It was observed that titration of Curc-gluc with α-synuclein monomer yielded very low heat values with low binding while, in case of oligomers, Curc-gluc showed significant binding. Addition of Curc-gluc inhibited aggregation in a dosedependent manner and enhanced α-synuclein solubility, which propose that Curc-gluc solubilizes the oligomeric form by disintegrating preformed fibrils and this is a novel observation. Overall, the data suggest that Curc-gluc binds to α-synuclein oligomeric form and prevents further fibrillization of α-synuclein; this might aid the development of disease modifying agents in preventing or treating PD.

Keywords: Alpha-synuclein, Parkinson's disease, curcumin-glucoside, oligomer, aggregation, diferulomethane, Thioflavin, Fluorescence, sonication, Tris buffer