A New Twist on the Mad Cow—Scientists Discover the Normal Prion Protein May Contribute Directly to Disease

By Jason Socrates Bardi

In a surprising twist on a timely topic, scientists at The Scripps Research Institute are presenting evidence that mad cow disease prions cannot kill neurons on their own and that normal, healthy cellular prion protein may be a direct accomplice in unleashing neuronal destruction.

Bovine spongiform encephalopathy (BSE), or mad cow disease, is caused by prions, a misfolded "scrapie" form of the normal cellular protein, which is found on the surface of human, sheep, and cow neurons. Prion infections are also implicated in one form of the same disease in humans, called Variant Creutzfeldt-Jakob Disease, an incurable condition that causes neurologic abnormalities, dementia, and eventually death.

BSE has caused widespread public concern when it has appeared in cattle in Europe, Canada, and most recently the United States, as it is believed that the disease is transmitted across species by the consumption of prions from a diseased animal's central nervous system.

Unlike most infectious diseases, the infectious material of mad cow and other prion disease is not a virus, bacteria, or some other pathogen, but a protein. Normally, prion proteins are expressed throughout the body and sit anchored onto the surfaces of cells in a wide variety of tissues, particularly on cells in neuronal tissue. They are something of an enigma because scientists do not know what they do there. But if the function of prions is mysterious, their malfunction is notorious.

"The prion protein," says Scripps Research investigator Anthony Williamson, Ph.D., "has a Jekyll and Hyde personality."

A New View of Normal Prions

Previously, scientists viewed the normal cellular prion protein as mere fodder that the scrapie prions would turn into more scrapie prions until an army of scrapies grew into a spongy mass, killing brain cells, and causing the neurological wasting that characterizes the disease.

Now, Williamson and his colleagues in the Department of Immunology at The Scripps Research Institute are telling another story.

In an upcoming issue of the journal Science, Williamson and his colleagues present evidence that scrapie prions cannot kill neurons on their own. They required normal cellular prions to be present.

Furthermore, Williamson and his colleagues discovered that they were able to induce catastrophic neurotoxicity in vivo without any scrapie prions at all by adding antibody molecules, which cross-linked the normal prion protein. Thus, engaging and activating the normal prion protein triggered the type of neurodegeneration that characterize BSE and variant Creutzfeldt-Jakob.

This suggests a possible mechanism for prion pathogenesis—that scrapie prions cross-link normal cellular prions, killing neurons in the process. Rather than being innocent bystanders until converted into scrapie prions, normal cellular prions may be essential ingredients for prion diseases like BSE.

While illuminating the mechanisms of disease, the findings also suggest caution to one possible approach to fighting prion diseases—administering antibodies or small molecules that will bind to the normal prion protein and prevent the scrapie prions from binding. It now appears that in cross-linking the normal prion protein, such a therapy may actually promote rapid spongiosis.

The research article, "Crosslinking Cellular Prion Protein Triggers Neuronal Apoptosis in vivo," is authored by Laura Solforosi, Jose R. Criado, Dorian B. McGavern, Sebastian Wirz, Manuel Sánchez-Alavez, Shuei Sugama, Lorraine A. DeGiorgio, Bruce T. Volpe, Erika Wiseman, Gil Abalos, Eliezer Masliah, Donald Gilden, Michael B. Oldstone, Bruno Conti, and R. Anthony Williamson and appears in Science Express on January 29, 2004. Science Express provides rapid electronic publication of selected papers in the journal Science. Print versions of these papers will appear in Science after several weeks. See: http://www.sciencemag.org/sciencexpress/recent.shtml.

The research was funded by the National Institutes of Health, the Department of Defense National Prion Research Program, and the Clark Fellowship in Neurophysiology from the Brain Research and Treatment Center, Scripps Clinic.

Go back to News & Views Index