Oxidized quercetin inhibits α-synuclein fibrillization

• Published in: Biochimica et biophysica acta Vol. 1830; no. 4; pp. 2872 - 2881
• Main Authors: Zhu, Min, Han, Shubo, Fink, Anthony L.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2013
• Subjects: Aggregation; alpha-Synuclein - chemistry; antioxidant activity; antioxidants; atomic force microscopy; dopamine; high performance liquid chromatography; Hydrophilicity; Inhibition; isomers; light scattering; Microscopy, Atomic Force; Oxidation-Reduction; oxidative stress; Parkinson disease; Parkinson's disease; Protein Multimerization; Quercetin; Quercetin - pharmacology; risk factors; α-Synuclein; Aggregation; α-Synuclein; Parkinson's disease; Inhibition; Hydrophilicity; Quercetin
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2012.12.027

α-Synucein is a small (14kDa), abundant, intrinsically disordered presynaptic protein, whose aggregation is believed to be a critical step in Parkinson's disease (PD). Oxidative stress is reported to be a risk factor for dopamine cell degeneration in PD. Flavonoids are suggested to be important antioxidant against oxidative stress. Flavonoids were reported to inhibit fibrillization and disaggregate the preformed fibrils of α-synucein, but the molecular mechanism was still not clear. Quercetin, a well-recognized flavonoid antioxidant, was tested for its inhibition of α-synucein aggregation by thioflavin T assay, light scattering measurement, size-exclusion high performance liquid chromatography, atomic force microscopy, etc. The pre-incubated quercetin exhibited a noticeably stronger inhibition behavior to the fibril formation than that of the freshly prepared. The inhibition is significant in the presence of ortho- and para-benzenediol isomers and inconsiderable in the presence of meta-isomer. The oxidized quercetin species (i.e., chalcantrione, benzyfuranone, quercetinchinone, and other derivatives) cause stronger inhibition than quercetin does because of the elevated polarity and hydrophilicity. Presence of quercetin disaggregates α-synucein fibrils, rather than oligomers and amorphous aggregations. Instead of the antioxidant activity, the 1:1 covalent binding of quercetin with α-synucein, and the increased hydophilicity of the covalently modified α-synucein oligomers or monomers, account for the inhibition of α-synucein fibrillation. Clarification of the molecular mechanism of the inhibition and disaggregation may help to screen safer and more effective flavonoid therapeutic in combating PD. ► Oxidized quercetin inhibits fibrillization of α-synucein more strongly than quercetin does. ► Quercetin disaggregates α-synucein fibrils. ► Quercetin inhibits fibrillization and stabilizes oligomers. ► Quercetin binds with α-synucein in 1:1 ratio. ► Increased hydrophilicity of quercetin and α-synucein adducts accounts for inhibition.