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Redox activity of α-synuclein–Cu is silenced by Zn_(7)-metallothionein-3

Meloni, Gabriele and Vašák, Milan (2011) Redox activity of α-synuclein–Cu is silenced by Zn_(7)-metallothionein-3. Free Radical Biology and Medicine, 50 (11). pp. 1471-1479. ISSN 0891-5849.

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The aggregation of α-synuclein (α-Syn), the major component of intracellular Lewy body inclusions in dopaminergic neurons of the substantia nigra, plays a critical role in the etiology of Parkinson disease (PD). Long-term effects of redox-active transition metals (Cu, Fe) and oxidative chemical imbalance underlie the disease progression and neuronal death. In this work, we provide evidence that a brain metalloprotein, Zn_(7)-metallothionein-3 (Zn_(7)MT-3), possesses a dynamic role in controlling aberrant protein–copper interactions in PD. We examined the properties of the α-Syn–Cu(II) complex with regard to molecular oxygen, the biological reducing agent ascorbate, and the neurotransmitter dopamine. The results revealed that under aerobic conditions α-Syn–Cu(II) possesses catalytic oxidase activity. The observed metal-centered redox chemistry significantly promotes the production of hydroxyl radicals and α-Syn oxidation and oligomerization, processes considered critical for cellular toxicity. Moreover, we show that Zn_(7)MT-3, through Cu(II) removal from the α-Syn–Cu(II) complex, efficiently prevents its deleterious redox activity. We demonstrate that the Cu(II) reduction by thiolate ligands of Zn_(7)MT-3 and the formation of Cu(I)_(4)Zn_(4)MT-3, in which an unusual oxygen-stable Cu(I)_(4)–thiolate cluster is present, comprise the underlying molecular mechanism by which α-Syn and dopamine oxidation, α-Syn oligomerization, and ROS production are abolished. These studies provide new insights into the bioinorganic chemistry of PD.

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Additional Information:© 2011 Elsevier Inc. Received 18 December 2010; revised 25 January 2011; accepted 6 February 2011. Available online 12 February 2011. We thank Dr. S. Chesnov (Functional Genomic Center, Zürich, Switzerland) for recording nano-ESI MS spectra. This work was supported by Forschungskredit der Universität Zürich Grant 54043901 (to G.M.) and by Swiss National Science Foundation Grant 31003A–1118884 (to M.V.).
Funding AgencyGrant Number
Forschungskredit der Universität Zürich54043901
Swiss National Science Foundation31003A-1118884
Subject Keywords:α-Synuclein; Metallothionein-3; Copper; Zinc; Reactive oxygen species; Parkinson disease; α-Synuclein oligomerization; Redox silencing; Copper–thiolate cluster; Free radicals
Issue or Number:11
Record Number:CaltechAUTHORS:20110531-100532722
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Official Citation:Gabriele Meloni, Milan Vasak, Redox activity of [alpha]-synuclein-Cu is silenced by Zn7-metallothionein-3, Free Radical Biology and Medicine, Volume 50, Issue 11, 1 June 2011, Pages 1471-1479, ISSN 0891-5849, DOI: 10.1016/j.freeradbiomed.2011.02.003.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:23832
Deposited By: Jason Perez
Deposited On:31 May 2011 20:58
Last Modified:03 Oct 2019 02:50

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