Neuronal growth‐inhibitory factor (metallothionein‐3): evaluation of the biological function of growth‐inhibitory factor in the injured and neurodegenerative brain

Abstract

Neuronal growth‐inhibitory factor, later renamed metallothionein‐3, is one of four members of the mammalian metallothionein family. Metallothioneins are a family of ubiquitous, low‐molecular‐weight, cysteine‐rich proteins. Although neuronal growth‐inhibitory factor shares metal‐binding and reactive oxygen species scavenging properties with the other metallothioneins, it displays several distinct biological properties. In this review, we examine the recent developments regarding the function of neuronal growth‐inhibitory factor within the brain, particularly in response to brain injury or during neurodegenerative disease progression.

Bioinorganic Chemistry of Alzheimer’s Disease

“…As a compensation, MT-1/ MT-2 is up-regulated by free Zn 2+ and by other stress factors 527,539,541,554 as observed in AD. 581,592,593,583 MT-3 regulation is initially periodic upon neuronal insult, 591 as described in section 6, and may be chronically downregulated in the advanced stage of AD if astrocytes, a possible target of early pathogenesis, 429 become dysfunctional. .…”

Crosstalk of reactive oxygen species and NF-κB signaling

“…Metallothioneins are low-molecular-weight, cysteine-rich proteins which bind to many different metals [58]. In addition to regulating metal toxicity, the cysteine residues in metallothioneins can scavenge…”

Neuronal growth‐inhibitory factor (metallothionein‐3): reactivity and structure of metal–thiolate clusters*

“…It is unlikely, however, that mammalian MTs contain such a cluster. Spectroscopic experiments on mammalian MT1 ⁄ 2 indicate that they contain Cu(I) 4 -CysS 6-9 , Cu(I) 6 -CysS [9][10][11] or Cu(I) 3 ⁄ 4 -Zn x CysS x clusters and hence have a distinctly different cluster organization. In all cases, Cu(I) shows a preference (at least partial) for binding to the N-terminal b-domain [4,7].…”

“…Although MT3 belongs to the MT family and hence shares the unusual properties of their metal-thiolate clusters, there are important differences between MT3 and the well-characterized MT1 ⁄ 2 [4]. Such chemical and structural differences are probably important for the biological roles of MT3, such as its growth-inhibitory activity, the non-inducibility of its gene by diverse metal ions and other compounds known to elicit the formation of MT1 ⁄ 2, its predominant localization in the central nervous system with an accumulation in zinc-enriched neurons, and its possibility of being excreted into the extracellular space [4,9,10]. Note, that the latter may not be restricted to MT3 as evidence is accumulating that MT1 ⁄ 2 also occurs extracellularly [4].…”