A New Twist on the Mad CowScientists Discover the
Normal Prion Protein May Contribute Directly to Disease
By Jason Socrates
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
"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
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 pathogenesisthat
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 diseasesadministering 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
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.