Neurotoxicity Research

, Volume 14, Issue 4, pp 317–328

Covalent arylation of metallothionein by oxidized dopamine products: A possible mechanism for zinc-mediated enhancement of dopaminergic neuron survival

  • Michelle A. Gauthier
  • Joseph K. Eibl
  • James A. G. Crispo
  • Gregory M. Ross
Article

DOI: 10.1007/BF03033856

Cite this article as:
Gauthier, M.A., Eibl, J.K., Crispo, J.A.G. et al. neurotox res (2008) 14: 317. doi:10.1007/BF03033856

Abstract

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 anti-oxidant-like properties due to their ability to scavenge free radicals with their multiple sulfhy-dryl 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 bothin 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.

Keywords

Parkinson’s diseaseBDNFCatecholamineOxidative stress6-Hydroxydopamine

Abbreviations

6-OHDA

6-hydroxydopamine

BDNF

brain-derived neurotrophic factor

DA

dopamine

MT

metallothionein

PD

Parkinson’s disease

TH

tyrosine hydroxylase

Copyright information

© Springer 2008

Authors and Affiliations

  • Michelle A. Gauthier
    • 1
  • Joseph K. Eibl
    • 1
  • James A. G. Crispo
    • 1
  • Gregory M. Ross
    • 1
  1. 1.Northern Ontario School of MedicineSudburyCanada