In addition, the study has revealed surprisingly large structural differences between natural prions and the closest synthetic analogs that scientists have created in the lab.
³We expected to find subtle differences, but we found major differences instead,² said Gerald Stubbs, professor of biological sciences at Vanderbilt University. ³Although we cannot say for certain that the differences we¹ve seen can explain why natural prions are so infectious, there is a good chance that they are closely related.²
The study, which was published online in the Proceedings of the National Academy of Sciences last week, was a joint effort of the Stubbs laboratory and that of Stanley Prusiner at the University of California, San Francisco, who received the Nobel prize for the discovery of prions.
³Our results will aid in attempts to create the infectious synthetic prions that are needed to figure out how prions work and ultimately to find cures for the diseases that they cause,² said the lead author of the study, Holger Wille, assistant adjunct professor of neurology in the Institute for Neurodegenerative Diseases, which is based at UCSF and directed by Prusiner.
Prusiner¹s group was the first one that succeeded in making infectious prions in the test tube. However, they are not nearly as infectious as the real thing. Six years ago, Prusiner contacted Stubbs, who is a world authority on determining the molecular structures of fibrous materials, and asked if he was interested in collaborating on an effort to characterize the detailed structure of prions. It didn¹t take much convincing. ³I¹ve always been interested in prions, so I readily agreed,² said Stubbs.
Prions, because of their association with mad cow disease, are the most notorious of the amyloids, which are insoluble clumps of fibrous protein that play a role in a number of neurodegenerative diseases, including Alzheimer¹s, Parkinson¹s and Lou Gehrig disease, as well as some other common illnesses, including type II diabetes. ³It is particularly difficult to determine the molecular structure of fibrous materials like these because they have an intrinsically high level of disorder,² Stubbs explained.
When viewed with an electron microscope, which can magnify images up to one million times, the natural and synthetic prions look nearly identical. They both clump together to form microscopic filaments. At a magnification of approximately one hundred thousand times, the only visible difference is the width of the filaments: the synthetic material shows a wider distribution of widths than the natural material.
The Stubbs lab used unconventional X-ray diffraction methods to get the first details of the molecular structures of natural prions and Prusiner¹s synthetic prions. The researchers found that the synthetic prions were shaped something like a ladder. Based on electron microscopic images, the Prusiner lab had proposed that the natural prions have a more complex, three-sided cylindrical shape, and the X-ray experiments supported this proposal.
³The natural, infectious prions are folded into a much more complicated shape,² said Stubbs. Proteins are molecules that are folded into shapes that determine their biological properties. Prions and the other amyloids are cases in which proteins are misfolded into shapes that interfere with normal biological processes. ³Normally, the cellular systems deal with misfolded proteins but, for some reason, these slip through the cracks,² he said.
Prions don¹t have any DNA in their make-up so they don¹t reproduce in a normal fashion. Instead, they spread by transforming proteins they come into contact with into prions by causing them to misfold.
³Our data on prion structure is an important step toward understanding prion infection,² said Stubbs, ³and understanding the process is essential before people can design drugs that restrict or prevent it.² The research was supported by grants from the National Institutes of Health, Fairchild Foundation, G. Harold and Leila Y. Mathers Foundation, the National Science Foundation and the U.S. Department of Energy.
For more news about Vanderbilt, visit the Vanderbilt News Service homepage on the Internet at www.vanderbilt.edu/News.
UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.
David F. Salisbury | Vanderbilt University
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