title: Curcumin modulates α-synuclein aggregation and toxicity.
abstract: In human beings, Parkinson's disease (PD) is associated with the oligomerization and amyloid formation of α-synuclein (α-Syn). The polyphenolic Asian food ingredient curcumin has proven to be effective against a wide range of human diseases including cancers and neurological disorders. While curcumin has been shown to significantly reduce cell toxicity of α-Syn aggregates, its mechanism of action remains unexplored. Here, using a series of biophysical techniques, we demonstrate that curcumin reduces toxicity by binding to preformed oligomers and fibrils and altering their hydrophobic surface exposure. Further, our fluorescence and two-dimensional nuclear magnetic resonance (2D-NMR) data indicate that curcumin does not bind to monomeric α-Syn but binds specifically to oligomeric intermediates. The degree of curcumin binding correlates with the extent of α-Syn oligomerization, suggesting that the ordered structure of protein is required for effective curcumin binding. The acceleration of aggregation by curcumin may decrease the population of toxic oligomeric intermediates of α-Syn. Collectively; our results suggest that curcumin and related polyphenolic compounds can be pursued as candidate drug targets for treatment of PD and other neurological diseases.
authors.affiliation: Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India 400076.
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Singh
authors.forename: Vasudha
authors.initials: V
authors.lastname: Kotia
authors.forename: Dhiman
authors.initials: D
authors.lastname: Ghosh
authors.forename: Ganesh M
authors.initials: GM
authors.lastname: Mohite
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Kumar
authors.forename: Samir K
authors.initials: SK
authors.lastname: Maji
mesh_terms: D045744:Cell Line, Tumor; D003474:Curcumin / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000502:physiology; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000633:toxicity*
chemical_list: C497604:SNCA protein, human; D051844:alpha-Synuclein; D003474:Curcumin