Mammalian Metallothionein-3: New Functional and Structural Insights

Abstract

Metallothionein-3 (MT-3), a member of the mammalian metallothionein (MT) family, is mainly expressed in the central nervous system (CNS). MT-3 possesses a unique neuronal growth inhibitory activity, and the levels of this intra- and extracellularly occurring metalloprotein are markedly diminished in the brain of patients affected by a number of metal-linked neurodegenerative disorders, including Alzheimer’s disease (AD). In these pathologies, the redox cycling of copper, accompanied by the production of reactive oxygen species (ROS), plays a key role in the neuronal toxicity. Although MT-3 shares the metal-thiolate clusters with the well-characterized MT-1 and MT-2, it shows distinct biological, structural and chemical properties. Owing to its anti-oxidant properties and modulator function not only for Zn, but also for Cu in the extra- and intracellular space, MT-3, but not MT-1/MT-2, protects neuronal cells from the toxicity of various Cu(II)-bound amyloids. In recent years, the roles of zinc dynamics and MT-3 function in neurodegeneration are slowly emerging. This short review focuses on the recent developments regarding the chemistry and biology of MT-3.

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

“…In the brain, metallothionein 3 (MT3) is one of the major players in maintain the homeostasis of zinc, which is chelated as metalthiolate clusters. MT3 regulates zinc in a copper-related manner, and the zinc in MT3 can exchange with copper in the Aβ-Cu complex and inhibit the oxidative damage caused by the Aβ-Cu complex, Zn 2+ can also protect sulfhydryl groups from oxidation in the cells [86]. Therefore, downregulation of zinc or MT3 as observed in the AD neurons can contribute to the oxidative damages.…”

Amyloids: Regulators of Metal Homeostasis in the Synapse

“…Studies by others and our group suggest that AβPs directly incorporate into the membrane and form channels (pores) that allow the passage of Ca 2+ and other cations, and that the resulting change in [Ca 2+ ] i may be a primary pathogenetic event in AβP neurotoxicity [110][111][112]. Neurotoxic peptide fragments of AβP, including AβP(1-40), AβP (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) and AβP , have been demonstrated to incorporate into artificial planar lipid membranes and form giant multi-level pores (~5 nS) with cation (including Ca 2+ ) selectivity [113][114][115]. To assess the validity of this amyloid channel hypothesis, we performed an electrophysiological study to examine whether AβPs form channels on neuronal cell membranes as well as on liposomes.…”

“…Metallothioneins (MTs), such as MT1, MT2, and MT3, also regulate Zn 2+ homeostasis [26]. MT3 is of particular interest because it is expressed in the brain, and is decreased in AD patient brains [27,28].…”

“…It is also possible that PrP C affects the production of AβP by providing Cu to APP. Carnosine (β-alanyl histidine), which is synthesized and secreted from glial cells [97,98], and MT3 [27,28] may also participate in the maintenance of metal homeostasis at the synapse.…”

Reappraisal of metallothionein: Clinical implications for patients with diabetes mellitus

“…Extracellular MT also stimulates immune cells to generate anti‐MT antibodies . However, several reviews and key original studies providing detailed information regarding the release and potential roles of extracellular MT under physiological and pathological conditions are available …”