Deadly to cattle and humans, prions may help other organisms survive, researchers find

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

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.