Covalent Arylation of Metallothionein by Oxidized Dopamine Products: a Possible Mechanism for Zinc-mediated Enhancement of Dopaminergic Neuron Survival

Metallothioneins are a group of low molecular weight proteins which can be induced upon exposure to metal ions, including Zn2+. These cysteine-rich proteins are believed to have antioxidant-like properties due to their ability to scavenge free radicals with their multiple sulfhydryl groups. Dopamine is a neurotransmitter that can form toxic quinone and semi-quinone products in an oxidative environment. While Zn2+ is known to be toxic to some neuron subtypes, here we report a beneficial effect of Zn2+ on dopaminergic neurons and identify a mechanism through which metallothionein may scavenge toxic dopamine oxidation products. Cultured embryonic neurons were treated with Zn2+, and the number of dopaminergic neurons surviving after two or three weeks in culture was determined. We demonstrate that under these conditions metallothionein is upregulated and is able to form covalent arylation products with dopamine and 6-hydroxydopamine both in vitro and in culture. These experiments suggest that Zn2+ enhances the survival of dopaminergic neurons, and we propose that as a mechanism, upregulated metallothioneins form covalent adducts with both dopamine and 6-hydroxydopamine, resulting in the observed neuroprotective effect of Zn2+ on these cells. As Zn2+ homeostasis and modulation of metallothionein expression are often markers of neurodegeneration, these studies may have significant implications for understanding the underlying basis of degenerative diseases involving dopaminergic neurons, including Parkinson's disease.