Metallothionein in the central nervous system: Roles in protection, regeneration and cognition

Abstract

Metallothionein (MT) is an enigmatic protein, and its physiological role remains a matter of intense study and debate 50 years after its discovery. This is particularly true of its function in the central nervous system (CNS), where the challenge remains to link its known biochemical properties of metal binding and free radical scavenging to the intricate workings of brain. In this compilation of four reports, first delivered at the 11th International Neurotoxicology Association (INA-11) Meeting, June 2007, the authors present the work of their laboratories, each of which gives an important insight into the actions of MT in the brain. What emerges is that MT has the potential to contribute to a variety of processes, including neuroprotection, regeneration, and even cognitive functions. In this article, the properties and CNS expression of MT are briefly reviewed before Dr Hidalgo describes his pioneering work using transgenic models of MT expression to demonstrate how this protein plays a major role in the defence of the CNS against neurodegenerative disorders and other CNS injuries. His group's work leads to two further questions, what are the mechanisms at the cellular level by which MT acts, and does this protein influence higher order issues of architecture and cognition? These topics are addressed in the second and third sections of this review by Dr West, and Dr Levin and Dr Eddins, respectively. Finally, Dr Aschner examines the ability of MT to protect against a specific toxicant, methylmercury, in the CNS.

Toxicity of Alzheimer's disease-associated Aβ peptide is ameliorated in a Drosophila model by tight control of zinc and copper availability

“…Indeed the human MT3 transgene co-expressed with Ab42 suppressed the Abmediated phenotype ( Figure 5E). Although it is still unclear whether reduced levels of metallothioneins, notably of the brain-enriched MT3, contribute to AD (Uchida et al, 1991; Erickson et al, 1994;Uchida, 1994), our results are consistent with earlier findings that metallothioneins have neuroprotective functions (Irie and Keung, 2003;Penkowa, 2006;Meloni et al, 2008;West et al, 2008).…”

The metastasis-promoting S100A4 protein confers neuroprotection in brain injury

“…Metallothionein I þ II (MTI þ II) is a major releasable neuroprotectant, similar to S100A4 found in astroglia and overexpressed in the excitotoxic hippocampus 33,34 . Strengthening the similarity, genetic deletion of MTI þ II enhances neurodegeneration and oxidative stress in the excitotoxicity model 33 .…”

“…Metallothionein I þ II (MTI þ II) is a major releasable neuroprotectant, similar to S100A4 found in astroglia and overexpressed in the excitotoxic hippocampus 33,34 . Strengthening the similarity, genetic deletion of MTI þ II enhances neurodegeneration and oxidative stress in the excitotoxicity model 33 . We investigated a possible link between the S100A4 and MTI þ II expression and found that the KA-induced MTI þ II upregulation was markedly lower in the S100A4 À / À mice, with the difference most pronounced in the hippocampal CA1 region (Fig.…”

Regulation of Intracellular Copper by Induction of Endogenous Metallothioneins Improves the Disease Course in a Mouse Model of Amyotrophic Lateral Sclerosis

“…MTs are a family of small, cysteine-rich proteins that bind copper ions through copper-thiolate clusters [13]. Four MT isoforms exist in mammals, 2 of which, MT-I and MT-II (MT-I/-II), are major isoforms that exert neuroprotection against copper dyshomeostasis [14].…”

“…MT-I/-II is a well-known antioxidant, and its neuroprotective effects may be mediated through the suppression of oxidative stress [13]. Oxidative stress has been implicated in the pathogenesis of mutant SOD1-linked ALS [40], and is exacerbated by intracellular copper dyshomeostasis.…”