NIH Research Matters
July 2, 2007
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.
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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About NIH Research Matters
Harrison Wein, Ph.D., Editor
Vicki Contie, Assistant Editor
NIH Research Matters is a weekly update of NIH research highlights from the Office of Communications and Public Liaison, Office of the Director, National Institutes of Health.