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UCSF scientists show prion shape affects nature of infection

18.03.2004


UCSF scientists have demonstrated for the first time that a change in the folded shape of a prion protein changes its infectious properties -- including the prion’s ability to jump "species barriers."



The research, based on studies of prion infectivity in yeast, solves one of the great puzzles about prions: If they are infectious proteins with no genetic material of their own and no ability to mutate genetically, how can a single prion exist in different strains that can cause different diseases? The puzzle has led some to doubt that a protein alone causes mad cow and related diseases.

To reconcile the existence of prion strains with the "protein-only" hypothesis of prion propagation, scientists had proposed that a single protein can misfold into multiple different infectious conformations: one for each different type of prion strain.


The new finding confirms this view. It shows that shape change accounts for strain differences, and it lays the groundwork for research to determine the physical differences that allow a prion to change shape and cause different diseases. Answers could lead to strategies to block the folding or its route to disease, the scientists say.

The UCSF discovery is published in the March 18 issue of Nature. A second paper in the same issue of the journal by scientists at Florida State University reaches similar conclusions.

A News and Views commentary in Nature on the two research findings concludes that the work firmly establishes the link between different prion forms and different prion strains.

A prion is thought to cause disease by inducing other proteins to adopt its contorted shape and form sheets called amyloids. UCSF’s Stanley Prusiner, MD, received the 1997 Nobel Prize in Physiology or Medicine for the discovery of prions and the underlying principles of their mode of action.

Different strains of the mammalian prion play important roles in determining the degree to which a prion is pathogenic. In mammals, different strains of the same prion protein cause mad cow disease, scrapie and the related Creutzfeldt Jacob Disease (CJD), all of which lead to debilitating neurological damage known as transmissible spongiform enchephalopathy.

Studying the possible link between mammalian prion shape and strains has proven very difficult, but three different prions have also been identified in yeast, a powerful model in research aimed at understanding human genetic mechanisms. The UCSF study applies the versatile organism to studies of proteins and prion infectivity.

"The existence of different prion strains has been one of the most fascinating and puzzling features of prion biology," said Jonathan Weissman, PhD, a Howard Hughes Medical Institute investigator and professor of cellular and molecular pharmacology at UCSF. Weissman is senior author of the paper.

"With these studies we now have compelling evidence that the ability of proteins to misfold into multiple amyloid forms constitutes the physical foundation of the strain phenomenon. The challenge now is to understand what distinguishes the different structures in the different prion strains, and how these different structures change a prion’s properties -- including how dangerous they are."

In their laboratory at UCSF’s Mission Bay campus, Weissman and his colleagues introduced misfolded forms of a yeast prion protein into normal (prion-free) yeast. The yeast cells were grown in conditions that cause normal yeast organisms to form small, red colonies, while yeast infected with prions, termed [PSI+], form colonies of different colors. They found that introduction of the misfolded prion form yielded yeast "infected" with the [PSI+] prion.

Like prions that cause mammalian disease, the prions in yeast naturally exist in several different forms or strains. To explore the link between prion strains and the conformation of the misfolded proteins in the amyloid sheets, the researchers first generated amyloids at different temperatures. Studies of the melting temperatures of the prions and their resistance to breakdown by enzymes indicated that the conditions generated prions with different physical properties.

Weissman and his colleagues also inserted a biophysical probe at regular intervals along the prion’s amino acid chain -- a kind of beacon that could be picked up by a technique called electron paramagnetic spectroscopy. This procedure demonstrated that the proteins generated at different temperatures have distinct shapes.

They then infected living yeast with the different conformations and found marked differences: Infection with amyloids formed at the lowest temperature led to the "strong," highly infectious [PSI+] strain, while infection with amyloids formed at the higher temperatures primarily produced an alternative [PSI+] strain, termed "weak." Once infected, the yeast could pass on these different prion strains to generation after generation.

The studies show that a single infectious protein can adopt different, distinct, self-propagating shapes and that these conformational differences underlie the differences in prion strains, the scientists conclude. Since earlier work in the Weissman lab had shown that different prion strains have different abilities to jump from one species to another, the new finding demonstrates that prion shape underlies this ability.

"Until now, it has been very difficult to distinguish which features that we see in a test tube are merely curiosities and which are truly fundamental to understanding prion biology," Weissman said.

"The key advance in these studies is that we can now create prions in a test tube from pure proteins and use them to ’infect’ yeast. We can now move seamlessly from in vitro experiments to understanding how prions function in living organisms, and this allows us to explore fundamental questions about how prions grow and spread including why prions are able sometimes to jump species barriers."

Lead author on the paper is Motomasa Tanka, PhD, postdoctoral scientist in Weissman’s lab. Co-authors are Peter Chien, PhD, a former graduate student in the lab; Roger Cooke, PhD, professor of biochemistry and biophysics at UCSF; and Nariman Naber, PhD, in Cooke’s lab.


The research was funded by the Howard Hughes Medical Institute, the National Science Foundation, the ARCS Foundation, the National Institutes of Health and the David and Lucille Packard Foundation.

Wallace Ravven | EurekAlert!
Further information:
http://www.ucsf.edu/

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