Antioxidative and neuroprotective effects of metallothioneins on dopaminergic neurons

Metallothioneins (MTs) are a family of low molecular weight, cysteine-rich, ubiquitous, and inducible intracellular proteins that bind to heavy metals such as zinc, copper, and cadmium, participating in metal homeostasis and detoxification. The mammalian MT family comprises four isoforms: MT-1, MT-2, MT-3, and MT-4. The two major isoforms, MT-1 and-2, are expressed in most organs including the brain. MT-1 and-2 help to regulate metal homeostasis in the brain, as well as neural protective functions in various pathological and inflammatory conditions. MT-3, called growth inhibitory factor, is mainly expressed in the central nervous system and decreased in the brain of Alzheimer's disease. Attention has been focused on MTs as radical scavengers because of their abundant thiol groups, which participate exclusively in the formation of metal-thiolate clusters. The reactive oxygen or nitrogen species (ROS/RNS), generated in the oxidation of an excess amount of dopamine (DA), is thought to play an important role in dopaminergic neurotoxicity. In contrast to the general oxidative stress, the pathogenecity of quinone formation has been recently received attention as dopaminergic neuron-specific oxidative stress. When the DA neurons are damaged, an excess amount of cytosolic DA exists outside of the synaptic vesicle is spontaneously oxidized and produces superoxide and DA/DOPA quinones. DA quinone conjugates with cysteine-residues on functional proteins to form quinoproteins. Therefore, intrinsic thiol molecule MTs could be a therapeutic tool against dopaminergic neurotoxicity to prevent DA quinone from binding to the sulfhydryl groups of cysteine on functional proteins by their conjugation with DA quinone. Indeed, our recent study showed that MT exerts protective effects against the long-term L-DOPA treatment-induced DA quinone neurotoxicity in parkinsonian mice by its quenching property of DA quinone. In this article, we primarily review recent studies from our and other groups on the antioxidative and neuroprotective roles of MTs against oxidative stress including DA quinone neurotoxicity in dopaminergic neurons.