Review
Metals and neuroscience

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Abstract

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.

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 molecular approaches; and because biochemical training has traditionally de-emphasized the role of metals in metabolic 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 diseases, revealing ionic Fe, Cu, Mn and Zn as key neurochemical factors whose interactions with protein targets induce reactions that appear closely relevant to disease pathophysiology. Here, I overview the major contributions to this newly developing field over the last twelve or so months.

Section snippets

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 descriptions to the metal ions of Cu, Fe, Zn and Mn.

One of the most common misunderstandings that is ventilated 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,

Familial amyotrophic lateral sclerosis, SOD1 and copper

The most intriguing development in this field is the elucidation of how a mutation of Cu/Zn SOD (SOD1) engenders a gain of function that changes this ubiquitous antioxidant into a marauder that causes an aggressive degenerative disorder, familial amyotrophic lateral sclerosis (FALS). There is now abundant literature on the oxidative insult caused by the FALS-linked SOD1 mutation 15, 16, as well as the formation of SOD1 aggregates in affected motor neurons and glia [17]. Understanding the

Metal-engendered oxidative stress and aggregating proteins: a general theory

From the study of the abnormal biochemistry of AD, FALS, CJD and cataracts, I propose a triad of features shared by these diseases: protein aggregation in neural tissue; oxidation of neural tissue mediated by redox-active metal ion interaction with a target protein; and functional demise. I propose that certain neurodegenerative diseases are caused by the abnormal interaction of metals that are enriched in neural tissue, with specific protein targets that are vulnerable to such interactions.

Conclusions

This is a fascinating time, when neuroscience investigators are teaching themselves the fundamentals of inorganic chemistry and oxygen chemistry, and combining these disciplines with molecular biology and protein chemistry to study abnormal metal–protein interactions close to the molecular origin of major neurological diseases. The possibility that the antioxidant enzyme systems that preserve life are also the most likely to become dysregulated by abnormal metal-ion interaction, and then to

Acknowledgements

This work is supported with funds from Prana Corporation, the Neuroscience Education and Research Foundation, American Health Assistance Foundation, National Health and Medical Research Council of Australia, and the National Insitute of Aging.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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