184 Data are now rapidly accumulating to show that metallochemical reactions might be the common denominator underlying Alzheimer’s disease, amyotrophic lateral sclerosis, prion diseases, cataracts, mitochondrial disorders and Parkinson’s disease. In these disorders, an abnormal reaction between a protein and a redox-active metal ion (copper or iron) promotes the formation of reactive oxygen species or radicalization. It is especially intriguing how the powerful catalytic redox activity of antioxidant Cu/Zn-superoxide dismutase can convert into a pro-oxidant activity, a theme echoed in the recent proposal that Aβ and PrP, the proteins respectively involved in Alzheimer’s disease and prion diseases, possess similar redox activities. Addresses Laboratory for Oxidation Biology, Genetics and Aging Unit, Massachusetts General Hospital East, 149 Thirteenth Street, Charlestown, MA 02129, USA; e-mail: bush@helix.mgh.harvard.edu Current Opinion in Chemical Biology 2000, 4:184–191 1367-5931/00/$ — see front matter © 2000 Elsevier Science Ltd. All rights reserved. Abbreviations 3HAA 3-hydroxyanthranilic acid 3HK 3-hydroxykynurenine AD Alzheimer’s disease apoE apolipoprotein E APP amyloid precursor protein BBB blood–brain barrier CCS copper chaperone of SOD CJD Creutzfeldt–Jakob disease FA Friedrich’s ataxia FALS familial amyotrophic lateral sclerosis GSH reduced glutathione GSSG oxidized glutathione MT metallothionein PD Parkinson’s disease ROS reactive oxygen species SOD superoxide dismutase TSE transmissible spongioform encephalopathy Introduction Until the 1990s, the neuroscience research community paid scant attention to the neurometabolism of metal ions. Apart from a great deal of work done on calcium, and some on magnesium, the neurobiology of the heavier metal ions did not arouse much interest as they were not notably linked to major disease syndromes. This outlook seems set to change dramatically over the coming decade, with a growing number of excellent publications pointing the way to a seminal relationship between Fe, Cu, Mn and Zn in the generation (or defense) of oxygen and protein radicals that mediate the major neurological diseases. There has been notable resistance in the mainstream of the neuroscience community to the appreciation of the importance of this emerging literature. This is probably because neuroscientists are not usually exposed to the basics of metallochemistry and oxidation chemistry during their training, where the emphasis is on cellular and mol- ecular approaches; and because biochemical training has traditionally de-emphasized the role of metals in metabol- ic reactions, which is why they have been pejoratively termed ‘trace metals’. This is a misnomer because the concentrations of Fe, Zn and Cu in the gray matter are in the same order of magnitude as Mg (0.1–0.5 mM) [1 •• ]. Data is rapidly emerging from research on separate dis- eases, revealing ionic Fe, Cu, Mn and Zn as key neurochemical factors whose interactions with protein tar- gets induce reactions that appear closely relevant to disease pathophysiology. Here, I overview the major con- tributions to this newly developing field over the last twelve or so months. The brain is a specialized organ that concentrates metals Fundamental to an appreciation of the interface between neuroscience and metallobiology is an awareness that the brain is a specialized organ that concentrates metal ions. For the purposes of this review, I will confine my descrip- tions to the metal ions of Cu, Fe, Zn and Mn. One of the most common misunderstandings that is venti- lated is that the neurological syndromes in which metals are implicated are hypothetically caused by toxicological exposure to Cu, Fe, Zn and Mn. In other words, ingestion or exposure to the metals causes an abnormal protein inter- action, which then causes the disease. It is important to clarify this misconception. In terms of total concentrations, the brain has more than enough of these metal ions in its tissue to damage or dysregulate numerous proteins and metabolic systems. For example, the concentration of Zn 2+ that is released during neurotransmission is ∼300 μM, which is more than sufficient to be rapidly neurotoxic in neuronal cell culture [2]. Therefore, the brain must have efficient homeostatic mechanisms and buffers in place to prevent the abnormal discompartmentalization of metal ions. Also, the blood–brain barrier (BBB) is relatively impermeable to fluctuating levels of plasma metal ions. It is known that several of the metal regulatory transport sys- tems are energy dependent (e.g. the Wilson’s disease Cu-ATPase). Therefore, damage to the BBB or energy compromise in the brain, are two characteristics of several neurodegenerative disorders that could perturb metal lev- els and lead to deranged protein behavior. Hence, there is no need to hypothesize toxic exposure to explain abnormal metal–protein interactions in vivo. There are two generic reactions of relevance to neurode- generative disease. Firstly, a metal–protein association Metals and neuroscience Ashley I Bush