Brittle Prions Found to Be More Infectious

UCSF scientists have discovered why some misfolded shapes of a prion protein are more infectious than others - differences that affect how readily prions can trigger abnormal folding in other proteins. The researchers found that the most infectious strains are more brittle, allowing the prion to fragment into smaller pieces, generating new "seeds," which spread infection more quickly. The research was published online June 28 by the journal Nature and will appear later in the print edition of the journal. The discovery was made by applying a new mathematical model to experiments with yeast prions. It suggests that drugs aimed at stabilizing destructive clumps of mammalian prions might prevent fragmentation and offer a particularly effective means of reducing the deadly damage of protein misfolding, the scientists say. Mammalian prions are known to cause fatal brain-destroying human diseases, such as Creutzfeldt-Jakob disease and kuru, and so-called mad cow disease and scrapie in livestock. The study was led by Jonathan Weissman, PhD, Howard Hughes Medical Institute (HHMI) investigator at UCSF and professor of cellular and molecular pharmacology. Weissman is also a UCSF faculty affiliate at the California Institute for Quantitative Biomedical Research (QB3). Weissman's lab earlier determined that the same yeast prion can exist in different strains that have different infectious effects. A similar strain phenomenon is known in mammalian prions. His lab has shown that prions are apparently benign in yeast cells, but the greater ease of studying them makes yeast prions a powerful model for understanding basic prion biology and the protein's physiological effect on cells. In the new research, his team exploited a relatively simple yeast prion system known as PSI+ to try to determine why different misfolded forms have such different effects on a cell. Their mathematical model described how a prion grows and divides in a cell. They then combined this model with experiments to explore what distinguishes "strong" prions from ones that have a relatively mild effect on a cell. Surprisingly, they found the strong strain does not differ from the weaker ones by its ability to grow more rapidly. Instead, it is much more brittle, and this brittleness allows it to be fragmented more easily and thereby to generate new seeds more quickly, and so trigger abnormal folding in other proteins. Weissman's lab plans to develop their model to more precisely describe how the prions' physical properties translate into physiological effects. They are also interested in analyzing the links between prions' protein molecular structure and their physical properties. Related Links: Nature