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Prion deadliness tied to division

Strain virulence in yeast stems from ability to divide, not grow, new study suggests

By | June 29, 2006

In a finding that may help explain why some conformations of misfolded proteins cause diseases, while others don't, researchers report in this week's Nature that the virulence of prions appears to be rooted in their ability to break apart and generate new seeds. These findings fly in the face of previous assumptions that prion virulence was linked to faster growth, the authors note. "It's a surprising finding," Guiseppe Legname, from the University of California in San Francisco, who did not participate in the study, told The Scientist. "But then afterwards when you think of it, it makes sense." Working in yeast, the researchers charted the differences between three different conformations of the same prion protein, and found that the strain with the most marked physiologic effects showed relatively slow growth. However, it was significantly more "brittle," causing the protein to easily divide and generate new seeds. A similar mechanism of infection may underlie transmissible spongiform encephalopathies (TSEs) such as Creutzfeldt-Jakob disease in mammals, the authors note. "Our results showed that the strongest prions are actually not the ones that grow the fastest but, ironically, the ones whose structure is more fragile," Jonathan Weissman, from the University of California in San Francisco, told The Scientist. "These are very general biophysical properties of proteins, and I think it's a reasonable hypothesis to think it might also occur in humans." The yeast prion Weissman's team chose to analyze is Sup53, a translation factor required by ribosomes to terminate polypeptide production. When adopting a prion state, Sup53 produces a defective termination phase, and generates what is known as the PSI+ phenotype, which can be screened by cell color and protein analysis. Different strains of the Sup53 prion affect PSI+ in variable degrees. "Our basic idea was to understand why different misfolded forms of the same protein have such drastically different physiologic effects," said Weissman. The team created three strains of the Sup53 prion in vitro. Using atomic force microscopy, they followed these particles' growth and division rates, then compared the results to the strains' effects when inserted into yeast. "Naively, we thought that the strong prions would be the ones that grow the fastest," said Weissman. "They turned out to be the ones that grew the slowest, but which had the most fragile structure." The authors suggest the same factors could explain prion virulence in mammals, perhaps leading to new therapeutic strategies that reduce mammalian prions' toxicity by preventing division. Guiseppe Legname, who studies the mammalian prion protein (Prp), noted that mammalian and yeast prions seem to behave similarly in folding and stability, but he hesitated to generalize the findings to the mammalian system. "Mammals and yeast are very different systems," he said. These findings "might be also true in mammals, but I don't want to anticipate too much," he said. "While in yeast you can reproduce in vivo what you found in the test tube with high fidelity, it's not the case in mammals. We don't know much about the biophysics of the mammalian prion, we can't anticipate their behavior in vivo, where many other molecules come into play -- the environment is completely different." Chih Yen King, who studies the structure of yeast prions at Taiwan's Academia Sinica, and who did not participate in the study, also indicated that it is still unclear how the infectious process takes place in mammals. "There are many different theories, some people say there are other factors besides the Prp protein, it's not very clear at the moment," he told The Scientist. "This study is a good confirmation of what happens in yeast. For mammals, we are not there yet." Clementine Wallace cwallace@the-scientist.com Links with this article Tanaka M. et al., "The physical basis of how prion conformations determine strain phenotypes," Nature, June 29, 2006. http://www.nature.com/index.html Fogarty M., "Prions -The terminators," The Scientist, July 28, 2003. http://www.the-scientist.com/article/display/13974/ Jonathan Legname and the Institute for Neurodegenerative Diseases. http://ind.medschool.ucsf.edu/ Jonathan Weissman http://www.hhmi.org/research/investigators/weissman.html King CY et al. "Protein-only transmission of three yeast prion strains," Nature, March 18, 2004. PM_ID: 15029195. Legname G, et al., "Strain-specified characteristics of mouse synthetic prions," PNAS, February 8, 2005. PM_ID: 15671162. Legname G, et al.: "Synthetic mammalian prions," Science, July 30, 2004. PM_ID: 15286374. Chih-Yen King http://www.imb.sinica.edu.tw/~cking/ Maher B., "Prion hypothesis proven?" The Scientist, April 21, 2005. http://www.the-scientist.com/article/display/22653/
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