A Basic Recipe for Prions
Prions have been among the most controversial of infectious disease
agents. These misshapen proteins have no DNA or RNA, so many researchers
have been skeptical of the idea that they alone can be responsible
for disease. Now, infectious prions have successfully been created
in the laboratory for the first time, providing insight into how
these deadly proteins form.
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The brain tissue of a person with Creutzfeldt-Jakob disease
has a sponge-like appearance. Image courtesy of Ermias
Belay, National Center for Infectious Diseases. |
Transmissible spongiform encephalopathies (TSE) are rare, fatal
diseases that cause the brain to develop lesions so that it looks
like a sponge. TSEs include "mad cow" disease in cattle, scrapie
in sheep, chronic wasting disease in deer and elk and Creutzfeldt-Jakob
disease in humans. Scientists have long thought that the brain
damage is caused by abnormal prion proteins that clump together
and accumulate in brain tissue. Normal forms of these proteins
are found on the surface of many types of cells, including brain
cells. However, even the best efforts to purify prions have been
plagued by contaminants, so it’s been difficult for researchers
to exclude the possibility that something else might really be
causing TSEs.
A research team at Dartmouth Medical School led by Dr. Surachai
Supattapone reported in the June 5, 2007, issue of Proceedings
of the National Academy of Sciences that they came upon a
way to generate infectious prions spontaneously from noninfectious
components. In work supported by The Burroughs Wellcome Fund and
NIH’s National Institute of Neurological Disorders and Stroke (NINDS),
they first purified a noninfectious protein called PrPC from
hamsters. A chemical analysis of their preparation showed only
PrPC plus some lipid molecules. By seeding the preparation
with infectious prions and some generic RNA made in the lab, they
could convert PrPC into its infectious prion form, PrPSc.
In the course of their experiments, the researchers also tested
a preparation that wasn’t seeded with infectious prions. To their
surprise, they found that PrPSc molecules spontaneously
appeared anyway. Once formed, those PrPSc molecules
propagated more PrPSc. Thinking they may have contaminated
their preparation with prions, they tested PrPC from
other labs and got the same results.
To test whether the PrPSc molecules they created were
infectious, the researchers next inoculated hamsters with the samples.
They found that the preparations all caused scrapie, whether from
seeded or unseeded samples.
These results are a major step forward in solving the mystery
of how infectious prions form in the first place. The type of RNA
molecule the researchers used to help the prion conversion along
was a polyanion—a molecule with repeated, negatively charged
units. Without it, PrPSc molecules didn’t form. This
result suggests that interactions between PrPC and polyanions
found naturally in the brain may contribute to spontaneous prion
formation. Understanding the role polyanions play in infectious
prion formation may bring scientists one step closer to being able
to prevent or treat prion diseases.
—by Harrison Wein
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