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Hunting the elusive prion
THE CULPRIT behind the so-called transmissible spongiform encephalopathies (TSEs), such as mad cow disease or the human version, Creutzfeldt-Jakob disease, is thought by many to be a misfolded protein called a prion. These misshapen molecules also have been linked to more common, non-infectious brain diseases such as Alzheimer's, Parkinson's, Huntington's and Lou Gehrig's.If prions truly are the culprits behind these diseases, their existence flies in the face of the conventional wisdom that only organisms with a genome (such as viruses or bacteria) can spread disease or perpetuate themselves in living cells. Not all scientists accept the "prion hypothesis," however. Although plenty of evidence hints that prions act alone to cause disease, no one has yet been able to conclusively prove this theory. JEKYLL-AND-HYDE PROTEINS Last week, a team of researchers reported in Science that they had accomplished an important variation on this theme using yeast cells. Jonathan Weissman and his colleagues at the University of California, San Francisco, proved that prions in yeast cells perpetuate themselves by inducing proteins to undergo Jekyll-and-Hyde-like conversions from their normal form into the misfolded prion shape. Weissman is optimistic that studying yeast prions is a key step toward developing much-needed treatments or prevention methods for prion diseases in mammals. "A major motivation for studying yeast prions is that we think the principles we learn about in this simple system will shed light on diseases like mad cow and even Alzheimer's disease," Weissman says.Stanley Prusiner of UCSF, first coined the term "prion" in Science in 1982. Although many considered the idea outrageous at first, scientists have been slowly warming to the idea that an agent without a shred of genetic material could cause disease. Proving the hypothesis, however, requires turning pure, normal proteins into prions and then putting them into cells. If the cells become infected, only then can scientists be sure they're dealing with an infectious agent. Researchers have been unable to complete this "gold standard" experiment successfully with mammals. It's relatively easy to induce TSE diseases in hamsters and mice by injecting them with purified brain tissue from other infected animals, but those results alone don't specifically prove that prions are the infectious agents. Human 'mad cow' cases rising Where scientists run into trouble is getting the mammalian proteins to flip spontaneously into their prion doppelgängers in the lab. This step is crucial for showing that the infectious material consists of prions, and nothing more. Currently, normal mammalian proteins just won't make the switch.Certain yeast proteins, however, are much more obliging. DUAL IDENTITIES IN YEAST In 1994, Reed Wickner, of the National Institute of Diabetes and Digestive Kidney Diseases, proposed in Science that a certain yeast protein seemed to misfold into a prion. Two years later, Susan Lindquist and her colleagues at the University of Chicago followed suit. They showed that, in its abnormal form, a prion protein called sup35 clumps together inside yeast cells and stops doing its basic job, which is helping to translate DNA into new proteins. These clumps were similar in important ways to the prion clumps found in the brains of animals and humans with TSEs or the non-infectious brain diseases like Alzheimer's. In brain tissue, the clumps cause holes to grow (hence the term "spongiform"), causing permanent and fatal damage.As in mammals, the change from normal to clumped proteins in yeast didn't seem to involve DNA. The genetic sequence for both the normal and prion forms of sup35 was exactly the same. These findings suggested that a protein can pass on a trait without any DNA involvement, but such a radical idea would require solid proof before scientists would consider the matter closed. SOWING BAD SEEDS Now, Weissman's team has managed to prove that yeast prions "infect" other yeast cells without the help of any other molecules. They switched pure sup35 protein into the prion state, enclosed the prions in tiny membrane bubbles called liposomes and fused the liposomes with yeast cells. The cells began to accumulate clumps of prions, a sure sign that the prion "seeds" had begun to exert their influence on the normal proteins in the cell.This is exactly what many scientists think prions do in mammals to cause brain diseases. It's also possible, however, that mammalian prions aren't quite so self-reliant. Scientists are still puzzling over why these proteins don't spontaneously convert into prions outside of living cells."The big question now is, can you get this to work with mammalian proteins? If not, what's missing? Is there some magic step we're overlooking, or do you need other ingredients [in the experiment] as well?" Weissman wonders. The explanation for why yeast proteins can convert spontaneously into prions, while mammalian proteins don't, could point researchers towards methods for stopping infections in humans, according to Weissman. If it turns out that mammalian proteins need the help of other molecules in order to make the switch, this dependency might be the prion's Achilles heel."These questions will open up whole new sources of strength for thinking about ways to prevent or treat these diseases," Weissman says.Thus, the hunt for the agent behind mad cow disease and its ilk may soon come to a close. Mammalian prions may still be poorly understood, but our new knowledge about their yeast counterparts strengthens the argument that prions are the infectious agents behind some extremely perplexing diseases. © 2000 by the American Association for the Advancement of Science © 1997-2000 Snap and its content providers. All rights reserved. |