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Scripps Florida scientists show 'lifeless' prions capable of evolutionary change and adaptation
Date:12/31/2009

espite the fact that they contain no nucleic acid genome.

Mammalian cells normally produce cellular prion protein or PrPC. During infection, abnormal or misfolded protein known as PrPSc converts the normal host prion protein into its toxic form by changing its conformation or shape. The end-stage consists of large assemblies (polymers) of these misfolded proteins, which cause massive tissue and cell damage.

"It was generally thought that once cellular prion protein was converted into the abnormal form, there was no further change," Weissmann said. "But there have been hints that something was happening. When you transmit prions from sheep to mice, they become more virulent over time. Now we know that the abnormal prions replicate, and create variants, perhaps at a low level initially. But once they are transferred to a new host, natural selection will eventually choose the more virulent and aggressive variants."

Drug Resistance

In the first part of the study, Weissmann and his colleagues transferred prion populations from infected brain cells to culture cells. When transplanted, cell-adapted prions developed and out-competed their brain-adapted counterparts, confirming prions' ability to adapt to new surroundings, a hallmark of Darwinian evolution. When returned to brain, brain-adapted prions again took over the population.

To confirm the findings and to explore the issue of evolution of drug resistance, Weissmann and his colleagues used the drug swainsonine or swa, which is found in plants and fungi, and has been shown to inhibit certain prion strains. In cultures where the drug was present, the team found that a drug-resistant sub-strain of prion evolved to become predominant. When the drug was withdrawn, the sub-strain that was susceptible to swainsonine again grew to become the major component of the population.

Weissmann notes that the findings have implications for the development of therapeutic
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Contact: Keith McKeown
kmckeown@scripps.edu
858-784-8134
Scripps Research Institute
Source:Eurekalert

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