1. Metals in brain, metal transport, storage and homeostasis

Metal ions are absolutely essential to fulfil a series of important biological functions in the brain, such as nerve transmission, muscle contraction and oxygen transport. The alkali metal ions Na⁺ and K⁺ play a crucial role in the transmission of nervous impulses. Ca²⁺ ions play an important role in signal transduction-increases in intracellular Ca²⁺ activated the ubiquitous eukaryotic Ca²⁺-binding protein calmodulin which in turn can bind to a large number of target enzymes to modify their activity. Zinc is a ubiquitous metal ion, which plays an important role both in catalysis and in the stabilization of the structure of many proteins, including zinc-finger proteins, many of which bind to DNA promoter sites. Zn metabolism itself seems to be regulated essentially through Zn-dependent control of transcription, translation and intracellular trafficking of transporters as well as its storage in metallothionein. It is likely that Zn homeostasis in humans requires the coordinated activity of members of several Zn transporter families, particularly those involved in Zn ingress and egress from cells and organelles. Zinc enhances GABA release via potentiation of α-amino-3-hydroxy-5-methyl-4-isoxalolepropionate (AMPA)/ kainate receptors in the CA3 region of the hippocampus, followed by a decrease in presynaptic glutamate release in the same region. Around 10% of total brain zinc is found distributed throughout the CNS in synaptic vesicles of glutamatergic neurones, although the function of this vesicular zinc is poorly understood.

Metalloenzymes containing iron, copper or manganese play extremely important roles in a number of key metabolic pathways within nervous tissues, They are, for example, involved in neurotransmitter synthesis (the Fe enzyme, tyrosine hydroxylase in the formation of dopa from tyrosine, the Cu enzyme dopamine β-hydroxylase which transforms dopamine to nor-adrenaline) and in neuroprotection (the Cu/Zn superoxide dismutase in cytosol and the Mn superoxide dismutase in mitochondria). However the presence of any of these redox-active metals in excess within localised regions of the CNS frequently spells disaster, with associated neurodegeneration.

Enormous advances have been made in the last 10 years in understanding iron homeosatasis, (See Crichton 2001), from the identification of genes and proteins involve in its uptake and transfer, e.g. DcytB, DMT1, Ireg1, modulation of their translation by IRP-1 and IRP-2, and proteins involved in its storage, ferritin and haemosiderin. However exactly how the brain regulates fluxes and storage of iron into neurons, oligodentrites, astrocytes and glial cells remains an enigma. In normal circumstances the iron content within the brain varies greatly from one region to another. Significantly greater iron concentrations, as μg/g protein, are found in the substantia nigra and the globus palidus than in liver (Götz et al., 2004), and other brain regions with high concentrations are the dentate gyrus, interpeduncular nucleus, thalamus, ventral pallidus, nucleus basilis and red nucleus (Figure 1). Regions of the brain associated with motor functions tend to have more iron than non-motor related regions This may explain why movement disorders are often associated with iron loading. The form in which this iron is incorporated into various proteins remains unclear, in oligodendrocytes it is bound to both H- and L-chain ferritin, in microglia to L-ferritin, while neurons contain mostly neuromelanin. In contrast astrocytes contain hardly any ferritin. H- and L-ferritin have different functions such that their specific locations might indicate specific biological roles. L-ferritin is predominantly involved with iron storage while H-ferritin is associated with stress responses as well as catalysing the oxidation of Fe²⁺ to Fe³⁺ via the ferroxidase centre. Transferrin is thought to transport iron within the brain, while other transport pathways involving non-transferrin-bound iron, NTBI, may be present. There appear to be at least two receptors in the brain for iron uptake, namely transferrin receptors, expressed exclusively in gray matter, and ferritin receptors present only in white matter.

Ceruloplasmin has long been thought to be a ferroxidase and it has been proposed that ceruloplasmin has a custodial role in vivo, ensuring that Fe²⁺ released from cells is oxidized to the potentially less toxic Fe³⁺ prior to its incorporation into apotransferrin (Lindley, 1996). The neurodegenerative disease aceruloplasminaemia is associated with the absence of Cu-ceruloplasmin due to the presence of inherited mutations within the ceruloplasmin gene. This condition results in disruption of iron homeostasis, with extensive iron accumulation in a number of tissues such as brain and liver. However, in these patients, as in aceruloplasminaemic mice, both copper transport and metabolism are normal, providing strong evidence against the role of ceruloplasmin as a major copper transporter (for a review see Nittis and Gitlin, 2002). It is most likely that copper is transported in serum bound to albumin.