Howard Hughes Medical Institute researchers have discovered that brittle prion particles break more readily into new “seeds,” which spread infection much more quickly. The discovery boosts basic understanding of prion infections, and could provide scientists with new ideas for designing drugs that discourage or prevent prion seeding, said the study’s senior author Jonathan Weissman, a Howard Hughes Medical Institute investigator at the University of California, San Francisco . Weissman and colleagues reported their findings on June 28, in an advance online publication 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.”