Fake Prion Can Infect Yeast

27 January 2000 7:00 pm

Scientists have created an artificial prion, a type of protein whose misshapen version is implicated as the cause of several fatal and infectious conditions, including "mad cow disease" and human Creutzfeldt-Jakob disease. The finding, reported in tomorrow's issue of Science, provides additional evidence that prion proteins by themselves are infectious, although skeptics remain unconvinced.

In their normal form, prion proteins are soluble. But according to the "prion only" theory of infection, trouble begins if their structure warps into an insoluble tangle. This abnormality can then be propagated from cell to cell because, when the misfolded version touches the normal one, it can trigger the same misfolding, thus causing the newly insoluble prions to clump. If this happens in nerve cells, for example, the clumped proteins can cause permanent damage. But because the prion hypothesis violates long-standing dogma that a DNA- or RNA-based genome is needed for infectivity, doubters insist that it is not yet proven: A virus or some other as-yet-unidentified microbe, they say, may team up with the prion protein to devastate the nervous system.

Further evidence for the prion-only hypothesis now comes from University of Chicago geneticist Susan Lindquist and postdoc Liming Li. Yeast can also carry prions, and the duo fused part of a yeast prion protein called Sup35 to a normal rat protein that controls the transcription of DNA into RNA. The hybrid protein, dubbed NMGR, had no trouble carrying out the normal protein's duties. But the researchers found that it could be switched to an abnormal prion form, and when that happened it was knocked out of commission. Most importantly, this alteration could be passed down from mother to daughter yeast cells. Not only that, but in the current issue of Molecular Cell, the Lindquist lab has identified a new yeast prion and shown that a segment of this protein also confers prionlike activity.

"The astonishing thing is that the prion property can be transferred to a totally different protein," says neuropathologist Adriano Aguzzi of the University of Zurich, Switzerland. According to Lindquist, "The new experiments provide an almost incontrovertible argument in favor" of the hypothesis that prions alone can be infectious--at least in yeast. But some prion skeptics argue that the new work may be irrelevant to mammals. The yeast prion model, notes Yale University neuropathologist Laura Manuelidis, "has nothing to do with infectious disease." She concedes, however, that genetically engineered prions of the type produced by the Lindquist team might help resolve the debate over the prion-only hypothesis in mammals.

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