Prions

PRIONS

The causative agents of the neurodegenerative diseases bovine spongiform encephalopathy (BSE), scrapie in sheep and Creutzfeldt –Jakob disease (CJD) in humans used to be referred to as slow viruses. However, it is now clear that they are caused by a distinct class of infectious agents termed prions that have unique and disturbing properties. They can be recovered from the brains of infected individuals as rod like structures which are oligomers of a 30 kDa glycoprotein. They are devoid of nucleic acid and are extremely resistant to heating and ultraviolet irradiation. They also fail to produce an immune response in the host. Just how such proteins can replicate and be infectious has only recently been understood. It seems that a glycoprotein (designated PrPc) with the same amino acid sequence as the prion (PrPsc) but with a different tertiary structure, is present in the membranes of normal neurons of the host. The evidence suggests that the prion form of the protein combines with the normal form and alters its configuration to that of the prion. The newly formed prion can then in turn modify the folding of other PrPc molecules. In this way the prion protein is capable of autocatalytic replication. As the prions slowly accumulate in the brain, the neurons progressively vacuolate. Holes eventually appear in the grey matter and the brain takes on a sponge-like appearance. The clinical symptoms take a long time to develop, up to 20 years in humans, but the disease has an inevitable progression to paralysis, dementia and death.

It is now clear that the largescale outbreak of BSE that began in the UK during the 1980s resulted from feeding cattle with supplements prepared from sheep and cattle offal. The recognition of this fact led to changes in animal feed policies and eventually to the imposition of a ban on the human consumption of bovine brain, spinal cord and lymphoid tissues that were considered to be potentially infectious. Unfortunately people had been consuming potentially contaminated meat for a number of years. Concerns that the agent had already been disseminated to humans in the food chain were realized in 1996 with the advent of a novel human disease that was called variant or vCJD. This condition was unusual as it attacked young adults with an average age of 30 rather than the 60yearolds who typically succumb to classical sporadic CJD. Studies on the experimental transmission of prions to mice provided evidence that vCJD represents infection by the BSE agent. The pathology in the mouse brain induced by the vCJD agent and the incubation time of the disease are different from that of classical CJD and very similar to that of BSE. Gel electrophoresis of the polypeptides from the brains of infected mice revealed that the different transmissible spongiform encephalitis agents have characteristic molecular signatures. These signatures are based on the lengths of proteaseresistant fragments and the glycosylation patterns on the prion molecules. The patterns from vCJD agent were very different patterns from those of the classical CJD but remarkably similar to those formed by BSE.

Since 1996 there has been a slow but gradual increase in the numbers of confirmed cases of vCJD. By November 2010 the number of deaths in the UK from vCJD had reached 170. As the average incubation time for vCJD is not yet known, it is difficult to estimate how many more cases will develop. The measures taken to protect the public will hopefully have prevented any further human infections, but sadly no effective treatment is available for those who have already contracted the disease.