Cutting edge

May 5, 2000

Research into prion proteins suggests how the spongiform encephalopathies, such as BSE, become pathogenic

One beneficial outcome of the BSE saga has been the re-emergence of interest in the transmissible spongiform encephalopathies (TSE). TSE diseases, which include a number of human conditions, are typified by progressive neurological degeneration, yet the definition of what the infectious agent is and does has been problematic. A key role for a single gene present in all vertebrates, the prion gene, is clear, but how the prion protein, which is found on the surface of nervous tissue, becomes pathogenic is disputed. Under a Medical Research Council-funded initiative and in collaboration with a group in Cambridge, we have been addressing these issues.

Using isolated genes, we translated prion protein in vitro and purified it in the presence or absence of copper. Copper has been linked with prion protein since the discovery that fragments of the protein could bind the metal, but verification that this was a property associated with the full-length protein found in normal nervous tissue was only recently obtained. We speculated that protein made in the presence of copper might take up a novel three-dimensional shape and reveal new biochemical properties. We subjected the purified proteins to a number of measures of protein shape and function. First, the prion protein with and without copper was analysed by spectroscopy, which showed the protein did indeed adopt a different shape when copper was present. Second, antibodies were used as molecular probes to recognise short stretches of the prion protein sequence; if the antibody binds then the region recognised must be accessible; if not, the target region must be folded into a form that cannot be accessed. Antibodies to some parts of the prion protein reacted differently on the two forms of protein. Finally, direct measurements of the number of copper atoms present in purified protein samples showed that the protein had acquired copper if it was present during the preparation. These data indicated that prion protein adsorbs copper from solution and, in its presence, folds to give a shape that may be different from the forms analysed to date.

Earlier work had shown that cells derived from mice in which the prion gene has been knocked out showed heightened sensitivity to cell death from biochemical stress. Perhaps the copper-bound prion protein could be the factor that helped to protect against stress-induced cell death. We found that the copper form of prion showed protection, the form made without copper failed. If we mutated the protein so that copper could not be bound, no protection was observed.

The new data do not address how the wild type non-pathogenic form of prion protein changes to the form found in disease, but we think they may indicate how disease occurs once normal prion is destabilised by infection. Protection against biochemical stress is essential for cell survival, and if normal prion protein is prevented from offering such protection, a slow degeneration of the affected cells will ensue. The role of prion as a metal-binding protein may hold the key to the start of TSE disease. Undoubtedly, ingestion of already diseased tissue triggers prion failur, but before the food chain is involved low-frequency sporadic TSE disease must occur. With copper at the heart of prion function, it is possible that imbalances in metal ion concentration in the environment lead to aberrant prion function and consequential disease. The understanding that prion protein contains and may use metal ions could underpin a new wave of research.

Ian Jones is professor of virology elect at the School of Animal and Microbial Sciences, University of Reading. His prion research was conducted in collaboration with David Brown of the University of Cambridge.

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