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Bulletin of the World Health Organization

Print version ISSN 0042-9686

Bull World Health Organ vol.81 n.7 Genebra Jan. 2003

http://dx.doi.org/10.1590/S0042-96862003000700019 

NEWS

 

Canadians find marker for prion diseases

 

 

Charlene Crabb

Paris

 

Researchers led by neurologist Neil Cashman at the University of Toronto have found a distinctive marker on the misfolded proteins responsible for bovine spongiform encephalopathy (BSE or mad cow disease), and other prion diseases in animals and humans. The discovery, reported on 1 June in Nature Medicine (online) could lead to better diagnostic tests and, possibly, vaccines or immunotherapies for the fatal, brain-destroying diseases.

 

 

The announcement of this finding came just 14 days after Canadian food inspection officials launched a massive programme to quarantine, test and cull beef cattle in three western provinces after a cow in Alberta tested positive for BSE. It is only the second case of BSE that has ever occurred in Canada. The first, in a bullock that had been imported from Britain in 1987, occurred in 1993. In the current case, some 1700 head of cattle have been slaughtered. Many of the carcasses were used to test for BSE in herds that may have had contact with the infected animal or contained its offspring. So far, no other diseased cows have been found.

If scientists succeed in developing a diagnostic test based on the recently discovered marker, the need to sacrifice animals to obtain brain tissue for testing will be eliminated. Instead, the misshapen prions could be fished out of a blood sample.

Prion protein is normally found in animals. Like all proteins, it is made up of a chain of amino acids that folds itself into a specific shape, which gives the molecule stability as well as a unique function. The function of prion proteins, which are found most abundantly in the brain, remains a mystery. When misfolded, however, they wreak havoc in the brain, causing cells to die, abnormal amyloid protein to build up, and other anomalies to occur.

Moreover, scientists think that misshapen prion protein acquires the ability to transform any normal prion protein that it contacts into the pathogenic version. "So prion infection is more like a crystallization process than biological replication," says Cashman. "But the end result is that normal protein in the brain is gradually and disastrously turned into the abnormal shape."

Cashman and his team reasoned that stretches of the amino acid chain buried within the nooks and crannies of a normal prion protein might be thrust to the surface once it refolded into the abnormal shape. If so, the exposed sections might contain unique combinations of amino acids that could be used to distinguish disease-causing prion protein from its normal counterpart. And that is just what the researchers found. A trio of amino acids consisting of two tyrosine molecules and an arginine showed up on synthetic or recombinant prion proteins that the scientists had deliberately misfolded in the laboratory. The team also demonstrated that antibodies that target the tyrosine-tyrosine-arginine trio, or epitope, bind to the misfolded prion proteins in the brains of prion-diseased cattle, sheep, elk, mouse and hamster models, and humans. But, the antibodies do not latch on to normal prion proteins in healthy brain tissue.

 

 

So far, antibodies have failed to detect misshapen prion proteins in blood, but the preparation of a diagnostic blood test based on the tyrosine-tyrosine-arginine epitope is under way. The Johnson & Johnson corporation has bought the rights to develop such a test for human prion diseases, which include variant Creutzfeldt–Jakob disease, the disease thought to result from eating BSE-tainted beef products. Similarly, IDEXX Laboratories, Inc., is working on a diagnostic blood test for prion diseases in animals.

Meanwhile, Cashman and his team are doing groundwork that could lead to vaccines or immunotherapies. In theory, the antibodies would bind to the three amino acids and thereby prevent the pathogenic protein from deforming the rest. In research funded in part by the hamburger giant, McDonald's Corporation, the scientists have immunized mice with the tyrosine-tyrosine-arginine molecule. Over the next few months, the rodents will be inoculated with misfolded prions. If the mice are protected from disease, it will open the door for testing the technique in larger animals and, possibly, humans. "It could be the royal road to containing and extinguishing prion epidemics including BSE, chronic wasting disease in elk and even sheep scrapie," says Cashman.