2005
DOI: 10.1074/jbc.m412621200
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Reversible Inhibition of α-Synuclein Fibrillization by Dopaminochrome-mediated Conformational Alterations

Abstract: Previous studies demonstrated that ␣-synuclein (␣-syn) fibrillization is inhibited by dopamine, and studies to understand the molecular basis of this process were conducted (Conway, K. A., Rochet, J. C., Bieganski, R. M., and Lansbury, P. T., Jr. (2001) Science 294, 1346 -1349). Dopamine inhibition of ␣-syn fibrillization generated exclusively spherical oligomers that depended on dopamine autoxidation but not ␣-syn oxidation, because mutagenesis of Met, His, and Tyr residues in ␣-syn did not abrogate this inhi… Show more

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Cited by 265 publications
(320 citation statements)
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“…AlphaͲsyn, however, does not possess a cysteine residue in its structure. Data from Norris et al(2005) [159] suggest an ionic interaction between dopamineͲquinone and residues 125Ͳ129 of alphaͲsyn. Dopaminemodification of alphaͲsyn seems to maintain small alphaͲsyn oligomers in a reactive protofibril conformation by inhibiting progression to form less reactive aggregates and this effect was more evident for alphaͲsyn mutant forms [160,161].…”
Section: Alphaǧsynuclein (Snca)mentioning
confidence: 99%
“…AlphaͲsyn, however, does not possess a cysteine residue in its structure. Data from Norris et al(2005) [159] suggest an ionic interaction between dopamineͲquinone and residues 125Ͳ129 of alphaͲsyn. Dopaminemodification of alphaͲsyn seems to maintain small alphaͲsyn oligomers in a reactive protofibril conformation by inhibiting progression to form less reactive aggregates and this effect was more evident for alphaͲsyn mutant forms [160,161].…”
Section: Alphaǧsynuclein (Snca)mentioning
confidence: 99%
“…Therefore, additional control experiments were performed by measurements in positive-ion mode. Tyrosine, which is structurally similar to DA but does not affect AS fibrillation 13 24,48 . Furthermore, Tyr binding does not induce changes in the CSD comparable to those observed with DA ( Fig.…”
Section: Da Binding Is Observed Preferentially With As In Partially Ementioning
confidence: 99%
“…DA has been shown to inhibit AS fibrillation and to promote aggregation into SDS-resistant oligomers 11 . It has been proposed that this process depends on DA oxidation but not on AS oxidation 13 . Other authors 14 suggested that the main mechanism of DA-dependent AS oligomerization is related to methionine oxidation.…”
Section: Introductionmentioning
confidence: 99%
“…The latter process occurs naturally in substantia nigral cells, where the aminochrome is a precursor of the characteristic pigment neuromelanin. However, dopaminochrome has also been shown to be responsible (229) for the inhibition of R-synuclein fibrillization seen for dopamine (230), suggesting that dopamine depletion in PD would enhance R-synuclein aggregation. Dopaminochrome and its one-electron-reduced semiquinone constitute an active redox cycling pair that is toxic to dopaminergic neurons in culture, resulting in hydroxyl radical production, mitochondrial damage, and necrotic cell death (231).…”
Section: Role Of Oxidative Stress In the Pathogenesis Of Pd And Modelmentioning
confidence: 99%