BSE, scrapie, and CJD: recent advances in research

Bovine spongiform encephalopathy (BSE) in cows, scrapie in sheep, and Creutzfeldt-Jakob disease (CJD) in humans are examples of prion diseases. The central event in the pathogenesis of these fatal disorders is hypothesized to be the post-translational conversion of a normal host protein of unknown function, termed PrPC into an abnormal isoform called PrPSc. The idea that protein alone can carry information sufficient to ensure its own propagation was an unprecedented challenge to the "central dogma" of molecular biology which essentially states that nucleic acids, not proteins, are the biological information carriers. The work that led to current understanding of prion diseases originated more than four decades ago. In the 1960s, Tikvah Alper and her co-workers reported that the scrapie agent was extremely resistant to treatments that normally destroy nucleic acids, but sensitive to procedures that damage proteins. Furthermore, the minimum molecular size needed in maintaining infectivity was too small to be a virus or other known infectious agent. These results led J. Griffith to propose that the material responsible for transmitting scrapie could be a protein that has the unusual ability to replicate itself in the body. Extensive work by Stanley Prusiner finally led to the purification of the PrP protein. For the next two decades, most research on prion diseases has focussed on the abnormal PrPSc and consequently, the functional role of PrPC has remained an enigma. Recent advances in the field of prion research, however, suggest that PrPC is a copper binding protein and has a modulating role in brain oxidative homeostasis. On the basis of in vitro studies by D. R. Brown at the University of Cambridge, it would appear that PrPC may act as an antioxidant enzyme in a similar manner to superoxide dismutase. The presence of the copper ion is essential for such a function.

Much recent evidence suggests that alterations in metallochemical processes could be a contributing factor for the pathological process in neurodegenerative disorders, including Alzheimer's disease and now possibly prion diseases. The PrPC protein has recently been found to have a region at its N-terminus, which is able to bind copper tightly and other metals, such as nickel, zinc and manganese, less tightly. One of the biochemical differences between the PrPC and PrPSc that was recognized very early is the surprising resistance of PrPSc to proteases (enzymes able to degrade proteins). In vitro studies have shown that if manganese ions replace the copper ions in the PrPC protein, it undergoes a structural change and becomes protease resistant. Furthermore, the binding of manganese to PrP dramatically reduces its superoxide-dismutase activity, suggesting that its cellular function may be affected under these conditions. Whether these in vitro changes brought about by different metal ions resemble the changes in PrP during prion disease is still to be confirmed, but the results are certainly suggestive. Research in this direction is progressing in several institutions in the UK at the moment.

High concentrations of metals are found in the brain and to prevent neuronal damage triggered by these elevated concentrations, the brain has evolved efficient mechanisms to regulate the availability of these metals. Metals are required for the normal functioning of the brain, such as the proper transmission of synaptic signals, which involve the release of zinc, copper and iron by neurons. At the same time, metals are an integral part of the cellular defense system, as they are often bound to antioxidant proteins and protect the brain from damage by free radicals. Although metals are essential to the normal functioning of the brain, perturbation in metal levels can upset cellular protein behaviour and possibly lead to neurological disorders. In Alzheimer's disease, for example, the levels of copper, zinc, and iron were found to alter in severely degenerated brain regions. In the hippocampus and amygdala regions, the levels of both zinc and iron were increased while the levels of copper were decreased.

In the 1970s, Pattison and Jebbett showed that when mice were fed with cuprizone, a copper chelator, it induced histopathological changes reminiscent of scrapie in sheep and further analysis indicated similar biochemical changes. Also a recent report by Mark Purdey showed that in the ecosystem supporting isolated clusters of sporadic prion diseases in Colorado, Iceland, and Slovakia, a consistent elevation of manganese concentration in relation to normal levels recorded in adjoining prion disease-free localities were detected. Evidence has also emerged concerning the metal content of the brains of animals and humans with prion diseases. The most alarming finding is preliminary evidence from two independent groups that CJD patients have a ten-fold increase in the levels of manganese in their brains. This increase is unprecedented in any other diseases—except cases of manganese poisoning—implying that high brain manganese might be a specific hallmark of prion diseases. This has prompted intensive work on the relationship between prion diseases and environmental pollution. It is proposed that in regions where manganese levels are abnormally high, the manganese may bind to the normal brain PrPC protein and alter its structure into the abnormal PrPSc form. Under these circumstances, the PrPC would lose its protective antioxidant function and predispose the brain to increased oxidative damage.

Many questions concerning the connection between metals and prion diseases remain to be answered. What is clear is that metals can be both beneficial and malicious to the structure and function of PrP. It is important to elucidate the mechanisms involved in these brain metal perturbations and their role in modulating the structure of PrP. Furthermore, it is also essential to determine the structural and functional changes induced by different metals on PrP at the molecular level and the resultant phenotypic features. Conclusive evidence that the loss of PrPC function contributes to prion diseases requires further experiments, possibly with animal models. What is certain is that the next few years will be crucial and exciting in deducing whether brain metal abnormalities constitute a mechanism in the development of prion disease.

See also BSE and CJD: Socio-economic impact and ethical issues; BSE and CJD; Slow virus and viral diseases