Metallothionein I + II expression and roles during neuropathology in the CNS.

INTRODUCTION MT PROTEINS In historical reports, a protein with high affinity for heavy metals and unusual cysteine abundance was discovered in 1957 in the equine kidney, and the protein was named metallothionein (MT) due to its high content of metals and sulfur (Kägi and Vallee, 1960; Margoshes and Vallee, 1957). Over the years, it was shown that MT constitutes a superfamily of quite unusual proteins, which are subdivided into MT classes and isoforms. The mammalian MTs all belong to class I; and the MT discovered in 1957 comprised the two major isoforms MT-I and MT-II (MT-I+II). MT-I+II are low-molecularweight (6-7 kDa), nonenzymatic proteins consisting of a single polypeptide chain of 61 amino acids characterized by a high content of sulfur (present as cysteine), zinc (Zn) and copper (Cu). In fact, 20 out of the 61 amino acids are cysteine residues, while aromatic amino acids and histidine are absent in MT-I+II (Ghoshal and Jacob, 2001; Klaassen et al., 1999). The spatial structure resembles a dumbell having two separate metal-thiolate clusters, the N-terminal β domain and the C-terminal α domain (Fischer and Davie, 1998; Kägi and Kojima, 1987). MT-I+II are regulated and expressed coordinately, and MT-I+II proteins are expressed ubiquitously throughout the animal kingdom in most tissues and cell types including in the CNS (Hidalgo et al., 1997b; Miles et al., 2000; Searle et al., 1984). In fact, MT-I+II are present not only in every animal phyla but also in prokaryotic and eukaryotic bacteria, fungi and plants, as MT-I+II proteins are very old in an evolutionary sense and have changed only little in the course of time (Ghoshal and Jacob, 2001; Kägi and Kojima, 1987; Klaassen, 1999). Besides the ubiquitous MT-I+II, another MT isoform called growth inhibitory factor (GIF) or MT-III has been described in CNS. However, MT-III/GIF regulation, expression and functions differ clearly from those of MT-I+II (Carrasco et al., 2003; Coyle et al., 2002). The fourth, known isoform MT-IV has not been shown in CNS.