Redox activity of α-synuclein–Cu is silenced by Zn_(7)-metallothionein-3
- Creators
- Meloni, Gabriele
- Vašák, Milan
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.
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.).Additional details
- Eprint ID
- 23832
- Resolver ID
- CaltechAUTHORS:20110531-100532722
- 54043901
- Forschungskredit der Universität Zürich
- 31003A-1118884
- Swiss National Science Foundation
- Created
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2011-05-31Created from EPrint's datestamp field
- Updated
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2021-11-09Created from EPrint's last_modified field