Small Prions More
Infectious Than Larger Ones
Scientists have found that small prions are much more infectious than large ones, yet, there is a lower size limit, below which infectivity is lost.
Prions consist primarily of an abnormal form of a protein molecule called PrP, and the most infectious prions are significantly smaller than the large thread-like deposits of PrP molecules readily seen in the diseased brains of infected individuals. Yet to be infectious, a prion must be much larger than the single malformed PrP molecule that has long been thought to be the basic unit of infectivity. The research was published recently in Nature and performed by scientists at the Rocky Mountain Laboratories (RML) in Hamilton, Mont.
Scientists have known that the size of infectious prions vary, but now, for the first time, the RML team has ranked them according to their efficiency at being infective.
Prions appear to be clusters of PrP molecules that look like crystals. They can grab normal, dissolved PrP molecules and convert them to a solid, crystal state, said RML senior researcher Byron Caughey, PhD.
"Although large prion particles can do this, and are infectious, you can infect many more individuals, or cause much more rapid disease in a single individual with an equivalent weight of small prion particles, Caughey said in a statement. "But our findings also suggest that if the PrP cluster is smaller than a certain minimum size, it becomes unstable and loses its infectious properties.
Normal PrP molecules found in many animals do not cause harm. But PrP molecules can become lethal and destroy the brain when they refold and gather into precisely ordered clusters. This basic infectious process is reminiscent of disease processes seen with other prominent neurological diseases, except that in each disease a different protein is involved.
The RML researchers are now trying to isolate the molecular components of the most infectious prions to analyze what else is present.
That approach included isolating aggregates of infectious prions from the brains of scrapie-infected hamsters and dispersing them into detergents.
Jay Silveira, PhD, then fractionated the prions, and inoculated them into hamsters. The RML scientists determined the masses of the prion particles and ranked their infectivity by tracking the number of days that passed until the hamsters showed symptoms of scrapie.
Caughey said dispersing and fractionating the prions were the most challenging parts of the experiment. "At a certain point, the particles become too small to be infectious and they can accidentally be destroyed, he said.
Prions cause transmissible spongiform encephalopathies (TSEs), such as Creutzfeldt-Jakob disease in humans, mad cow disease in cattle, scrapie in sheep and chronic wasting disease in deer and elk.
Patricia A. Doyle, PhD
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