The flavonoid baicalein inhibits fibrillation of alpha-synuclein and disaggregates existing fibrils.
The aggregation of alpha-synuclein has been implicated as a critical step in the development of Parkinson's disease. Parkinson's disease is a progressive neurodegenerative disorder caused by the loss of dopaminergic neurons from the substantia nigra; currently, no cure exists. Baicalein is a flavonoid with antioxidant properties; upon oxidation, it forms several products including quinones. We show here that low micromolar concentrations of baicalein, and especially its oxidized forms, inhibit the formation of alpha-synuclein fibrils. In addition, existing fibrils of alpha-synuclein are disaggregated by baicalein. The product of the inhibition reaction is predominantly a soluble oligomer of alpha-synuclein, in which the protein molecules have been covalently modified by baicalein quinone to form a Schiff base with a lysine side chain in alpha-synuclein. The binding of baicalein was abolished by conversion of the Tyr residues into Phe, demonstrating that Tyr is involved in the interaction of alpha-synuclein with baicalein. In disaggregation baicalein causes fragmentation throughout the length of the fibril. These observations suggest that baicalein and similar compounds may have potential as therapeutic leads in combating Parkinson's disease and that diets rich in flavonoids may be effective in preventing the disorder.
Zhu
Min
M
Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, USA.
Rajamani
Sudha
S
Kaylor
Joanna
J
Han
Shubo
S
Zhou
Feimeng
F
Fink
Anthony L
AL
D000693:Anaerobiosis; D052160:Benzothiazoles; D002942:Circular Dichroism; D004926:Escherichia coli / Q000378:metabolism; D044950:Flavanones; D005419:Flavonoids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008027:Light; D008239:Lysine / Q000737:chemistry / Q000378:metabolism; D018625:Microscopy, Atomic Force; D008970:Molecular Weight; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D011487:Protein Conformation; D011809:Quinones / Q000737:chemistry / Q000378:metabolism; D012542:Scattering, Radiation; D012995:Solubility; D013050:Spectrometry, Fluorescence; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet; D051843:Synucleins; D013844:Thiazoles / Q000737:chemistry; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism; D051844:alpha-Synuclein
D052160:Benzothiazoles; D044950:Flavanones; D005419:Flavonoids; D009419:Nerve Tissue Proteins; D011809:Quinones; C497604:SNCA protein, human; D051843:Synucleins; D013844:Thiazoles; D051844:alpha-Synuclein; C009462:thioflavin T; C038044:baicalin; D014443:Tyrosine; C006680:baicalein; D008239:Lysine