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 Prusiner's 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.

"The natural, infectious prions are folded into a much more complicated shape," 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. "Normally, the cellular systems deal with misfolded proteins but, for some reason, these slip through the cracks," he said.

Prions don't have any DNA in their make-up so they don't reproduce in a normal fashion. Instead, they spread by transforming proteins they come into contact with into prions by causing them to misfold.

"Our data on prion structure is an important step toward understanding prion infection," said Stubbs, "and understanding the process is essential before people can design drugs that restrict or prevent it."

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.

Source: Vanderbilt University