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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. https://resolver.caltech.edu/CaltechAUTHORS:20110531-100532722

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.freeradbiomed.2011.02.003DOIUNSPECIFIED
http://www.sciencedirect.com/science/article/pii/S0891584911000931PublisherUNSPECIFIED
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.).
Funders:
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
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20110531-100532722
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
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:31 May 2011 20:58
Last Modified:03 Oct 2019 02:50

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