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Inhibition of α‐synuclein fibrillization by dopamine analogs via reaction with the amino groups of α‐synuclein
Author(s) -
Li HongTao,
Lin DongHai,
Luo XiaoYing,
Zhang Feng,
Ji LiNa,
Du HaiNing,
Song GuoQiang,
Hu Jun,
Zhou JiaWei,
Hu HongYu
Publication year - 2005
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2005.04792.x
Subject(s) - chemistry , moiety , stereochemistry , catechol , quinone , benzoquinone , dopamine , adduct , amino acid , hydroquinone , biochemistry , biology , organic chemistry , neuroscience
Fibrillization of α‐synuclein (α‐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 α‐Syn fibrillization by a mechanism where the oxidation products (quinones) of DA analogs react with the amino groups of α‐Syn chain, generating α‐Syn–quinone adducts. It is likely that the amino groups of α‐Syn undergo nucleophilic attack on the quinone moiety of DA analogs to form imino bonds. The covalently cross‐linked α‐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 α‐Syn, suggesting that the oligomeric intermediates are the major elements that are toxic to the neuronal cells. This finding implies that the reaction of α‐Syn with DA is relevant to the selective dopaminergic loss in PD.