Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-48196
Meloni, G; Vasák, M (2011). Redox activity of α-synuclein-Cu is silenced by Zn(7)-metallothionein-3. Free Radical Biology and Medicine, 50(11):1471-1479.
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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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|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
|DDC:||570 Life sciences; biology|
|Deposited On:||07 Jun 2011 10:09|
|Last Modified:||27 Nov 2013 19:14|
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