Redox activity of α-synuclein-Cu is silenced by Zn7-metallothionein-3

The aggregation of alpha-synuclein (alpha-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 (Zn7MT-3), possesses a dynamic role in controlling aberrant protein-copper interactions in PD. We examined the properties of the alpha-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 alpha-Syn-Cu(II) possesses catalytic oxidase activity. The observed metal-centered redox chemistry significantly promotes the production of hydroxyl radicals and alpha-Syn oxidation and oligomerization, processes considered critical for cellular toxicity. Moreover, we show that Zn7MT-3, through Cu(II) removal from the alpha-Syn-Cu(II) complex, efficiently prevents its deleterious redox activity. We demonstrate that the Cu(II) reduction by thiolate ligands of Zn7MT-3 and the formation of Cu(I)(4)Zn4MT-3, in which an unusual oxygen-stable Cu(I)(4)-thiolate cluster is present, comprise the underlying molecular mechanism by which alpha-Syn and dopamine oxidation, alpha-Syn oligomerization, and ROS production are abolished. These studies provide new insights into the bioinorganic chemistry of PD. (C) 2011 Elsevier Inc. All rights reserved.