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Unravelling the mysteries of the prions

One of the microscope images of human cerebral tissues affected by the new variant of Creuztfeld-Jakob disease (nvCJD) presented by Robert Will and his colleagues, the co-signatories in 1996 of the famous Lancet article which sparked off the mad cow crisis in the UK. It is a portion of cerebellar cortex containing a large build-up of prionic proteins (in brown).

Some 45 EU-funded research projects are endeavouring to explain and combat 'mad cow disease', and scientists are busy working on research targeted on TSEs (transmissible spongiform encephalopathies). Prions, a new type of infectious agent, will require much more basic research before their secrets are revealed.

The neurodegenerative phenomenon caused by transmissible spongiform encephalopathies (TSEs) - so called because under the microscope the brain looks like a sponge with small holes - was identified a long time ago in both human beings and animals.
These diseases, which are always fatal, result in a
loss of motor control followed by dementia and

possibly paralysis. Nobody thought that crossing the species barrier was possible until in 1986 in the United Kingdom a new TSE appeared: BSE (bovine spongiform encephalopathy) or 'mad cow disease'. Epidemiological surveys quickly showed that, via animal meal, sheep scrapie could infect cattle.

Transmission confirmed

Ten years later the Scottish researcher Robert Will and his team described a new variant of Creutzfeldt-Jakob disease (nvCJD) that had been observed in the UK. They thought this form of the disease could be due to exposure to the BSE agent. The announcement was a bombshell. In the early 1980s an American neurologist, Stanley Prusiner, put forward the hypothesis that TSEs are transmitted by a single protein (earning him a Nobel prize in 1997). A new type of infectious agent called a prion (proteinaceous infectious particle) involves an ordinary protein of the organism known as PrP that has undergone a change of conformation. The protein then becomes hydrophobic, aggregates and resists the normal degradation mechanism. It thus builds up in the brain and causes neuron destruction.

Two sets of questions

This atypical mechanism raises a number of questions that were referred to the European Group on Research into BSE set up by the European Commission under Charles Weissmann of Imperial College in London, one of the leading specialists in the field of prions(1). Two sets of questions were identified. The first concerns the practical aspects of BSE. Has it really been transmitted to human beings? How can we estimate the risk of transmission? Which tissues are infected? How can diagnostic, inactivation and treatment methods be developed? The second set of questions concerns basic research. What is the nature of the infectious agent, how does it multiply, what are its pathogenesis and transmission mechanisms, specificity, susceptibility factors, etc.? The Commission launched an action plan on these research topics with a budget of EUR 50 million.

'It is very probable that the protein is associated with the infectious agent,' believes Dominique Dormont, a member of the Standing Committee of the European Group on Research in BSE. 'It is probable that the protein is itself the infectious agent, but we cannot be certain. Nor is there any certainty about the normal function of the PrP protein in the organism since genetically modified mice are not affected when it is removed.

'Concrete results are now appearing in epidemiology, and Europe has excellent diagnostic means and remarkable TSE surveillance. A network bringing together all the European laboratories working on prions has made it possible to establish interfaces between human and veterinary medicine. Once the infectious agent has been finally identified, molecular biology techniques will make it possible to proceed very quickly. Nevertheless, not all the problems will be resolved, and there will still be a need for further lengthy work. A public health problem such as spongiform encephalopathies can only be resolved by a breakthrough in basic research.'

(1) See Transmissible Spongiform Encephalopathies: the European Initiative, Catalogue of projects published by the 'Quality of Life and Management of Living Resources' Programme, European Commission - EUR 19369 - ISBN 92-828-9581-5

- Action plan for research into Bovine Spongiform Encephalopathies (BSE) and other prion diseases
- Collaborative Study Group
- Extended European Collaborative Study Group

Maria-José Vidal-Ragout, Research DG
Fax : +32-2-2955365
E-mail : maria.vidal-

Webites concerning Creutzfeldt-Jakob Disease:

1. Cerebral cortex affected by nvCJD with in the centre an amyloid prionic protein surrounded by a spongiform formation.

2. In brown, build up of specific prionic proteins of nvCJD in the basal ganglia.

3. Tissue of the posterior part of the thalamus affected by nvCJD exhibiting multiplication of astrocytes (in brown).