Jan. 24, 2000 Molecular studies in yeast have yielded surprising evidence that the contorted proteins known as prions, often deadly to cattle and humans, may serve a beneficial role in some organisms, and possibly in humans. By analyzing the gene sequences of yeast and more complex organisms, researchers at UC San Francisco have also found evidence that prions might be far more common than had been previously suspected.
The scientists also searched for and discovered a yeast species containing more than one kind of prion-forming protein, the first time a search has netted multiple prions in the same organism.
The discoveries and analysis are published in the January 21 issue of the journal Cell.
Prions' capacity to replicate in the brains of cattle and humans is thought to cause deadly or debilitating disease. But the researchers have detected the prion-forming trait intact in distantly related yeast species spanning 300 million years of evolution, suggesting prions perform a function important to yeast survival, since traits conserved over evolutionary time tend aid survival. Other researchers have found that yeast with prions known as PSI+ are more resistant to certain environmental insults than those lacking prions, hinting at a possible prion role in yeast survival.
The research also sheds light on the mechanism underlying the "species barrier" that usually prevents prions in one species from infecting other species. The barrier has been thought to prevent the transmission of scrapie and mad cow disease from livestock to humans, but recently researchers found alarming evidence that in some cases prions from cattle may infect other species, including humans.
The research in Cell shows that at least in yeast, the species barrier is an inherent property of prions and does not require assistance from a helper protein, or chaperone. The specificity, the researchers found, results form a small, well defined region on the prion surface, makng it an attractive potential target for drugs to bind the prions and prevent them from spreading.
In their experiments, the UCSF scientists developed a powerful genetic system for rapidly testing the ability of a protein to change shape into a prion and to propagate this form. The system can also test for related protein changes involved in Alzheimer's, Parkinson's and other human diseases caused by malformed aggregating proteins.
The researchers cloned and characterized the portion of the yeast protein - called Sup35 - that controls aggregation into sheet-like prion structures. They did this for a range of budding yeasts, the group that includes the kind used for centuries in baking and brewing.
Using their genetic system for testing prion function, they were able to show that despite the long evolutionary distance separating the various yeast species, the ability of Sup35 protein to form a prion state was strongly conserved. They then used the system to detect a new yeast prion, suggesting that many species may contain more than one prion type.
Since their analysis shows prions to be more widespread than had been thought and casts prions in a new, possibly more helpful light, the scientists considered what advantages the aggregating proteins might offer organisms.
The ability to form prions allows a cell to restrict activity of a specific protein indefinitely, without ever losing the potential to restore its original activity, they point out. If the prion form of the protein is passed on to progeny, this new trait will be passed on as well. Normally, heritable changes in protein function result from mutations in an organism's DNA. Such mutations might be beneficial under certain environmental conditions, say high temperatures, but once the DNA has mutated, the organism cannot readily revert to its original genetic makeup to adapt, for example, to a seasonal temperature drop
By contrast, because prions can change a protein's function without affecting the genes that code for it, the protein can revert back to its original function, either spontaneously or with the help of molecular chaperones, the researchers write. The increased flexibility could allow organisms to respond more easily to environmental change.
"Basically, a prion-based inheritance lets an organism continuously monitor its environment and in a manner reminiscent of Lemarkian inheritance, respond to changes in the environment and pass these changes on to its progeny," said Jonathan Weissman,assistant professor of cellular and molecular pharmacology at UCSF and senior author of the Cell paper.
The discovery of a new prion-forming region in a protein not before associated with prions supports the possibility that multiple prions could propagate independently in the same cell. These and other findings suggest that prion-based inheritance might play an important role not just in disease but in normal physiology, they point out.
In order for a prion to serve a regulatory role in the cell, it must propagate without interfering with other proteins, the scientists write. The remarkable specificity in prion growth which leads to the species barrier could also prevent different prions in the same cell from interacting and forming multi-protein aggregates, they conclude.
Co-authors with Weissman on the paper are graduate students Alex Santoso, Peter Chien and Lev Z. Osherovich, all in cellular and molecular pharmacology at UCSF. Chien is also in the graduate group in biophysics.
The research was funded by the Searle Scholars Program, the David and Lucile Packard Foundation, the National Institutes of Health and predoctoral fellowships funded by the National Science Foundation and the Howard Hughes Medical Institute.
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