( A similar strain phenomenon has been d...)Brittle prions are more infectious

A similar strain phenomenon has been described for mammalian prions. More generally, even in noninfectious diseases involving protein misfolding, like Alzheimer's and Parkinson's diseases, the same protein can misfold into more than one shape with some forms being toxic and others benign. However, Weissman said, it was not understood how different conformations cause different physiological effects.

As part of the studies published in Nature, the researchers created a mathematical model that enabled them to describe the growth and replication of prions according to the physical properties of the prion protein. To validate that model in yeast, they then created in a test tube, infectious forms of the prion protein in three different conformations and introduced them into yeast cells. They then correlated the strength of infectivity of each prion with its physical properties and compared their results to those predicted by their mathematical model.

According to Weissman, the researchers found that the slowest-growing conformation seemed to have the strongest effect in producing protein aggregates inside cells. "But we knew from our model that growth was only half of the equation," said Weissman. "The other key feature was how easy it was to break up the prion and create new seeds, and this propensity to seed could be an important determinant of the prion's physiological impact. And that is what we found experimentally -- that the slower growth of that conformation was more than compensated for by an increased brittleness that promotes fragmentation."

According to Weissman, the importance of a prion's brittleness, or "frangibility," to its physiological effects has both basic research and clinical implications. "Investigators trying to develop synthetic prions as a research model for mammalian prions have had a very hard time getting a high degree of activity," he said. "Part of the reason may be that they were trying to create forms that were
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Source:Howard Hughes Medical Institute

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