Gene variation resists mad cow

WASHINGTON -- Some people have a genetic variation that may help them resist the human form of mad cow disease, a study in mice suggests. But when infection does occur the disease takes a different form, meaning there may be unrecognized cases in the population, British researchers say.

This novel form of the brain-wasting disease hasn't yet been found in humans. But it has been observed in laboratory mice, leading scientists to urge a study of human autopsies to see if people also are affected.

"It's always difficult to extrapolate from laboratory animals to humans, but I think it's very likely that there's going to be more than one form of the disease" that affects people, Jonathan D. F. Wadsworth of University College London, said in a telephone interview.

Known as BSE in cattle, the disease that destroys the brain raised great concern when a form if it passed to humans in England in the 1980s and 1990s. It has killed more than 140 people in Great Britain and at least 10 others in other parts of the world. The only U.S. death, in June, was a woman who had been infected in England several years earlier.

When BSE is passed into humans it is known as variant Creutzfeldt- Jakob disease, or vCJD. There is also a brain-wasting disease called sporadic Creutzfeldt-Jakob disease which occurs in humans, but is not caused by BSE. Both, however, are caused by proteins -- called prions -- which fold incorrectly and result in brain damage.

Wadsworth's team, working with lab mice, uncovered a third, novel form of the disease, which also damages the brain but produces deposits there that differ in extent and location from the already- known forms of the illness.

The affected mice did not show any outward symptoms of disease, but Wadsworth noted that the life span of laboratory mice is only about two years.

"It may be they don't live long enough to generate symptoms," he said.

The misfolded protein involved in the disease is called PrP and, depending on a genetic difference, it can exist in two forms in humans: M129 (methionine) and V129 (valine).

The researchers found that mice carrying human PrP M129 could become infected with vCJD, while those with V129 resisted the disease. When the resistant mice did become infected, though, it was with the new novel form of the disease.

Their findings were reported in Thursday's issue of the journal Science.

Dr. Rudy Castellani, director of neuropathology at Michigan State University Clinical Center, commented that "the most alarming point raised in this paper is the experimental evidence that there may be (types of vCJD) lurking in the population, unrecognized as BSE- associated CJD."

On the other hand, he added, it's good news that they verified the suspicion that subjects with V129 are resistant to variant CJD.

The human form of the disease has been diagnosed based on certain suppositions about the disease type it would cause, noted Dr. Robert Petersen of the Case Western Reserve School of Medicine. "The paper suggests, based on the mouse model, that other phenotypes ... may be generated." This would have implications for studying the prevalence of the illness, he said.

"If we understood how V129 really interfered with prion formation, we might be able to mimic the process therapeutically," suggested Dr. William Siward James of the University of Oxford in England. He called it surprising that the resistant mice that did succumb to the disease developed a different form.

Castellani, Petersen and James were not part of Wadsworth's research team.

The study was funded by the United Kingdom Medical Research Council and the European Commission.

On the Net: Science: www.sciencemag.org

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