UCSD. US: Chronic wasting disease (CWD) an infectious disease caused by
prions affects North American elk and deer, but has not been observed
in humans. Using a mouse model that expresses an altered form of the
normal human prion protein, researchers at University of California, San
Diego School of Medicine have determined why the human proteins aren’t
corrupted when exposed to the elk prions. Their study, published Feb. 23
in the Journal of Clinical Investigation, identifies a small loop in the human prion protein that confers resistance to chronic wasting disease.
“Since the loop has been found to be a key segment in prion protein
aggregation, this site could be targeted for the development of new
therapeutics designed to block prion conversion,” said Christina
Sigurdson, DVM, PhD, associate professor at UC San Diego and UC Davis
and senior author of the study.
Prions aren’t microorganisms like bacteria or viruses; they’re simply
protein aggregates. Some prion diseases are caused by an inherited
genetic mutation, while others are caused by exposure to infectious
prions in food. Acquired prion diseases are triggered when a foreign,
misfolded prion protein causes the body’s own natural prion proteins to
misfold and aggregate. In addition to chronic wasting disease, examples
include scrapie and bovine spongiform encephalopathy (or "mad cow
disease") in animals and variant Creutzfeldt-Jakob disease in humans. In
humans, prion diseases can cause a variety of rapidly progressive
neurological symptoms, such as difficulty walking and speaking, and
dementia. These diseases are 100 percent fatal and there is currently no
effective treatment.
“We suspected that a loop in the human prion protein structure may
block the elk prions from binding, as the sequences did not appear to be
compatible,” Sigurdson said.
To test this hypothesis, Sigurdson and her team developed a
transgenic mouse that expresses a prion protein that’s identical to the
human version — except for a small loop, which they swapped out for the
elk prion sequence. When these mice were exposed to the elk prions, they
developed chronic wasting disease.
In contrast, control mice expressing the normal human prion sequence
resisted infection when exposed to same materials — just as humans seem
to, even those who consume venison meat.
“This finding suggests that the loop structure is crucial to prion
conversion and that sequence compatibility with the host prion protein
at this site is required for the transmission of certain prion
diseases,” Sigurdson said.
Co-authors of this study include Timothy D. Kurt, Cyrus Bett, Jun
Liu, Tom Yang, UC San Diego; Lin Jiang, David Eisenberg, UC Los Angeles
and Howard Hughes Medical Institute; Natalia Fernández-Borges, CIC
bioGUNE, Spain; Terry R. Spraker, Colorado State University, Fort
Collins; Joaquín Castilla, CIC bioGUNE and Basque Foundation for
Science, Spain; and Qingzhong Kong, Case Western Reserve University.
This research was funded, in part, by the National Institutes of
Health (grants NS055116, NS069566, U54AI0359 and AG029430), national
grants from Spain and the Morris Animal Foundation.