Inhibition of alpha-synuclein fibrillization by dopamine analogs via reaction with the amino groups of alpha-synuclein. Implication for dopaminergic neurodegeneration.
Fibrillization of alpha-synuclein (alpha-Syn) is closely associated with the formation of Lewy bodies in neurons and dopamine (DA) is a potent inhibitor for the process, which is implicated in the causative pathogenesis of Parkinson's disease (PD). To elucidate any molecular mechanism that may have biological relevance, we tested the inhibitory abilities of DA and several analogs including chemically synthetic and natural polyphenols in vitro. The MS and NMR characterizations strongly demonstrate that DA and its analogs inhibit alpha-Syn fibrillization by a mechanism where the oxidation products (quinones) of DA analogs react with the amino groups of alpha-Syn chain, generating alpha-Syn-quinone adducts. It is likely that the amino groups of alpha-Syn undergo nucleophilic attack on the quinone moiety of DA analogs to form imino bonds. The covalently cross-linked alpha-Syn adducts by DA are primarily large molecular mass oligomers, while those by catechol and p-benzoquinone (or hydroquinone) are largely monomers or dimers. The DA quinoprotein retains the same cytotoxicity as the intact alpha-Syn, suggesting that the oligomeric intermediates are the major elements that are toxic to the neuronal cells. This finding implies that the reaction of alpha-Syn with DA is relevant to the selective dopaminergic loss in PD.
Li
Hong-Tao
HT
Key Laboratory of Proteomics, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Lin
Dong-Hai
DH
Luo
Xiao-Ying
XY
Zhang
Feng
F
Ji
Li-Na
LN
Du
Hai-Ning
HN
Song
Guo-Qiang
GQ
Hu
Jun
J
Zhou
Jia-Wei
JW
Hu
Hong-Yu
HY
D003432:Cross-Linking Reagents / Q000737:chemistry / Q000494:pharmacology; D004298:Dopamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D010084:Oxidation-Reduction; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology; D059808:Polyphenols; D011487:Protein Conformation / Q000187:drug effects; D011809:Quinones / Q000737:chemistry / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D051843:Synucleins; D051844:alpha-Synuclein
D003432:Cross-Linking Reagents; D005419:Flavonoids; D009419:Nerve Tissue Proteins; D010636:Phenols; D059808:Polyphenols; D011809:Quinones; D051843:Synucleins; D051844:alpha-Synuclein; D004298:Dopamine