Deadly To Cattle And Humans, Prions May Help Other Organisms Survive, Researchers Find

The scientists also searched for and discovered a yeast species containingmore than one kind of prion-forming protein, the first time a search has nettedmultiple prions in the same organism.

The discoveries and analysis are published in the January 21 issue of thejournal Cell.

Prions' capacity to replicate in the brains of cattle and humans is thought tocause deadly or debilitating disease. But the researchers have detected theprion-forming trait intact in distantly related yeast species spanning 300million years of evolution, suggesting prions perform a function important toyeast survival, since traits conserved over evolutionary time tend aidsurvival. Other researchers have found that yeast with prions known as PSI+ aremore 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 "speciesbarrier" that usually prevents prions in one species from infecting otherspecies. The barrier has been thought to prevent the transmission of scrapieand mad cow disease from livestock to humans, but recently researchers foundalarming evidence that in some cases prions from cattle may infect otherspecies, including humans.

The research in Cell shows that at least in yeast, the species barrier is aninherent property of prions and does not require assistance from a helperprotein, or chaperone. The specificity, the researchers found, results form asmall, well defined region on the prion surface, makng it an attractivepotential target for drugs to bind the prions and prevent them from spreading.

In their experiments, the UCSF scientists developed a powerful genetic systemfor rapidly testing the ability of a protein to change shape into a prion andto propagate this form. The system can also test for related protein changesinvolved in Alzheimer's, Parkinson's and other human diseases caused bymalformed aggregating proteins.

The researchers cloned and characterized the portion of the yeast protein -called Sup35 - that controls aggregation into sheet-like prion structures. Theydid this for a range of budding yeasts, the group that includes the kind usedfor centuries in baking and brewing.

Using their genetic system for testing prion function, they were able to showthat despite the long evolutionary distance separating the various yeastspecies, the ability of Sup35 protein to form a prion state was stronglyconserved. They then used the system to detect a new yeast prion, suggestingthat many species may contain more than one prion type.

Since their analysis shows prions to be more widespread than had been thoughtand casts prions in a new, possibly more helpful light, the scientistsconsidered what advantages the aggregating proteins might offer organisms.

The ability to form prions allows a cell to restrict activity of a specificprotein indefinitely, without ever losing the potential to restore its originalactivity, they point out. If the prion form of the protein is passed on toprogeny, this new trait will be passed on as well. Normally, heritable changesin protein function result from mutations in an organism's DNA. Such mutationsmight be beneficial under certain environmental conditions, say hightemperatures, but once the DNA has mutated, the organism cannot readily revertto its original genetic makeup to adapt, for example, to a seasonal temperaturedrop

By contrast, because prions can change a protein's function without affectingthe genes that code for it, the protein can revert back to its originalfunction, either spontaneously or with the help of molecular chaperones, theresearchers write. The increased flexibility could allow organisms to respondmore easily to environmental change.

"Basically, a prion-based inheritance lets an organism continuously monitorits environment and in a manner reminiscent of Lemarkian inheritance, respondto changes in the environment and pass these changes on to its progeny," saidJonathan Weissman,assistant professor of cellular and molecular pharmacology atUCSF and senior author of the Cell paper.

The discovery of a new prion-forming region in a protein not before associatedwith prions supports the possibility that multiple prions could propagateindependently in the same cell. These and other findings suggest thatprion-based inheritance might play an important role not just in disease but innormal physiology, they point out.

In order for a prion to serve a regulatory role in the cell, it must propagatewithout interfering with other proteins, the scientists write. The remarkablespecificity in prion growth which leads to the species barrier could alsoprevent different prions in the same cell from interacting and formingmulti-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 pharmacologyat UCSF. Chien is also in the graduate group in biophysics.

The research was funded by the Searle Scholars Program, the David and LucilePackard Foundation, the National Institutes of Health and predoctoralfellowships funded by the National Science Foundation and the Howard HughesMedical Institute.