Prion data suggest BSE link to sporadic CJD

Predicting the number of cases of Creutzfeldt–Jakob disease (CJD) in people as a result of transmission of bovine spongiform encephalopathy (BSE) has just got more difficult.

Whereas it was thought that BSE only caused a new form of the disease called variant CJD (vCJD), a study in mice from a team led by John Collinge at University College London suggests that it may also cause a disease indistinguishable from the commonest form of classical, or 'sporadic', CJD (E. A. Asante et al. EMBO J. 21, 6358–6366; 2002). If the group's mouse model is relevant to the human disease, the results also suggest that the true extent of infection may be difficult to assess because of the large number of asymptomatic carriers.

The latest work uses mice engineered to carry the human gene for a cell-membrane protein called PrP. Prion diseases occur when PrP is converted to the abnormal 'prion' form, PrP^Sc. Collinge has developed a test, based on a standard western blot for analysing proteins, to study PrP^Sc extracted from the brain. This previously showed disease caused by BSE or vCJD to give a characteristic molecular signature that is distinct from sporadic CJD (J. Collinge, K. C. L. Sidle, J. Meads, J. Ironside and A. F. Hill Nature 383, 685–690; 1996).

In their latest experiments, Collinge and his team injected material from the brains of cows with BSE or people with vCJD directly into the brains of two strains of mice with a human PrP genotype known as 129MM. Almost 40% of the British population has this genotype. In one mouse strain, those that became infected showed the usual BSE pattern in the western blot. But in the other, Collinge's team tested 11 mice infected with BSE material using the western blot. Ten of them showed a pattern consistent with sporadic CJD.

The number of cases of sporadic CJD have been rising in Britain since the 1970s, and this had been attributed to better monitoring for the condition. But in July, researchers led by Adriano Aguzzi of the University Hospital Zurich reported a sudden increase in sporadic CJD figures in Switzerland in 2001, and suggested that infection with BSE might be to blame (see Nature 418, 266; 2002). Collinge's new data provide worrying molecular evidence that BSE might be to blame for the rise in sporadic CJD.

In previous experiments, Collinge had injected BSE and vCJD material into mice with another human PrP genotype, known as 129VV. The new data are thought to be more relevant to the transmission of BSE because all of the known human victims of vCJD have the 129MM genotype. Another worrying finding is that the 129MM mice seem to be more susceptible to developing a subclinical infection, with no obvious symptoms.

If a large pool of the British population is carrying a subclinical BSE infection, this would have serious consequences for the potential transmission of the disease, for instance through contaminated surgical instruments. And although laboratory mice are short-lived, infected humans might go on to develop the disease later in life.

The UK Department of Health, which has been briefed by Collinge on his findings, says that it will ask its Spongiform Encephalopathy Advisory Committee to consider the results closely at its next meeting in February. Collinge says that an urgent nationwide screening of tonsil material is needed to get a better estimate of the level of infection in the population.