Variant Prion Protein Causes Infection But No Symptoms
Finding Could Have Implications for Alzheimer’s
Disease
Abnormal prion proteins are little understood disease
agents involved in causing horrific brain-wasting diseases
such as Creutzfeldt-Jacob disease in people, mad cow
disease in cattle and chronic wasting disease in deer
and elk. Now, new research suggests that a variant form
of abnormal prion protein — one lacking an “anchor” into
the cell membrane — may be unable to signal cells
to start the lethal disease process, according to scientists
at the Rocky Mountain Laboratories (RML), part of the
National Institute of Allergy and Infectious Diseases
(NIAID) of the National Institutes of Health.
“This work provides novel insights into how prion and
other neurodegenerative diseases develop and it provides
tantalizing clues as to how we might delay or even prevent
such diseases by preventing certain cellular interactions,” notes
NIAID Director Anthony S. Fauci, M.D.
A paper describing the research was released online
today by the journal Science. RML virologist
Bruce Chesebro, M.D., directed the project. Other key
co-authors from the Hamilton, MT, RML laboratory include
Richard Race, D.V.M., and Gerald Baron, Ph.D. Their
collaborators included Michael Oldstone, M.D., and Matthew
Trifilo, Ph.D., of The Scripps Research Institute in
La Jolla, CA, and Eliezer Masliah, M.D., of the University
of California, San Diego (UCSD).
Drawing on experimental concepts first developed at
RML a decade ago, the research team exposed two groups
of 6-week-old mice to different strains of the agent
that causes scrapie, a brain-wasting disease of sheep.
Within 150 days of being inoculated with the natural
form of scrapie prion protein, all 70 mice in the control
group showed visible signs of infection: twitching,
emaciation and poor coordination. In contrast, the scientists
observed 128 transgenic mice — those engineered
to produce prion protein without a glycophosphoinositol
(GPI) cell membrane anchor — for 500 to 600 days
and saw no signs of scrapie disease. Subsequent electron
microscopic examinations at UCSD, however, confirmed
that they produced amyloid fibrils, an abnormal form
of prion protein, and that they even had brain lesions.
More remarkably, according to Dr. Chesebro, the diseased
brain tissue resembled that found in Alzheimer’s disease
rather than in scrapie.
Chesebro mentions two theories as to why the transgenic
mice did not show symptoms of illness despite being
infected:
- The host cell might require the GPI anchor to receive
the “toxic signal” from the abnormal prion protein
- The plaques might be less toxic than the non-plaque
form of prion protein clumps
In either case, more time might be required to produce
disease due to the reduced toxicity, Dr. Chesebro says.
“There was so much about this research that surprised
us and gave us ideas to pursue,” says Dr. Chesebro. “First,
the mice didn’t get sick. That’s very significant. Second,
the dense accumulations of scrapie plaque in the brain
resembled the plaque seen in Alzheimer’s, but it wasn’t
toxic,” which might support more recent concepts about
plaque in Alzheimer’s patients. “Previously, most researchers
thought plaques were the toxic component of Alzheimer’s
that kills neurons, and many treatments focus on removing
the plaques. But what if the plaques are inert, as they
were in this research? What if only small clumps are
toxic?”
If this hypothesis proves correct, Dr. Chesebro says,
the ongoing research could eventually alter scientists’ views
on preventing prion diseases, shifting emphasis away
from stopping the production of prion protein clumps
and toward preventing interactions with prion protein
anchored to cells, or learning to direct abnormal prion
protein accumulations to specific parts of the brain
where they will not produce symptoms.
“Abnormal prion protein by itself may not be rapidly
lethal — in these mice it wasn’t,” Dr. Chesebro
says.
![Image of Prion Proteins with the caption stating Abnormal prion proteins (red stain) also appear as plaques (green stain) in the brains of scrapie-infected mice expressing anchorless prion proteins.](https://webarchive.library.unt.edu/eot2008/20090201104217im_/http://www2.niaid.nih.gov/NR/rdonlyres/834FBBD0-9862-459C-BD90-45ADBBB3A90E/0/ChesebrophotoJune2005.jpg) |
Abnormal prion
proteins (red stain) also appear as plaques
(green stain) in the brains of scrapie-infected
mice expressing anchorless prion proteins. |
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