Some proteins can adopt a rigid, prion conformation, capable of converting other proteins of the same type to the new shape. These prions can form amyloids, causing the diseases associated with PrP. Because one prion can change other proteins into prions, prion disease can pass between animals like an infection.

But prions aren’t all bad. “We really think that prions are a bet-hedging device,” said Simon Alberti of the Whitehead Institute, joint first author on the Cell paper along with Randal Halfmann of the Massachusetts Institute of Technology. Should a clump of yeast suddenly find itself in a new environment—landing in a puddle, for instance—some proteins might switch to the prion state, altering or eliminating their usual function. Some of these changes would be detrimental, but some might be beneficial, allowing a few cells to survive in its newly waterlogged surroundings. Supporting this hypothesis, Lindquist’s lab previously found that one yeast prion is formed when the cells are exposed to high stress (Tyedmers et al., 2008). “It’s really a way to safeguard against future conditions,” Alberti said. “When the environmental conditions change, these cells with the prion could have an advantage over cells without the prion.”

In budding yeast, prions can pass from the mother cell to the bud, seeding new prions in the daughter. This prion “inheritance” is akin to the infectious transmission of PrP in animals. This protein-based mother-to-daughter cell information transfer knocks nucleic acid off its pedestal as the sole mediator of inheritance. “The whole thought of proteins serving as carriers of transmissible information sounds quite controversial for the ‘DNA-minded’ researchers of our century,” wrote Yury Chernoff of the Georgia Institute of Technology in Atlanta, and editor-in-chief of the journal Prion, in an e-mail to ARF. Yet scientists suspected proteins of carrying heritable information from the time of Darwin to the 1940s when Oswald Avery, Colin MacLeod, and Maclyn McCarty, in their classic experiment, showed that purified DNA could mediate bacterial transformation (Avery et al., 1944). “It’s like we’ve gone full circle,” said Sina Ghaemmaghami, who studies prions at the University of California, San Francisco.

When Lindquist and colleagues began the work they describe in Cell, there were three known and one potential prions in budding yeast, Saccharomyces cerevisiae. (A fourth has since been discovered; Du et al., 2008). These proteins share a glutamine- and asparagine-rich amino-terminal domain. Based on this and other features common to prions, the researchers scanned the yeast genome for proteins with similar sequences. They identified approximately 200 candidates, and characterized 100 of those in further detail. Nineteen of those could form prions in vitro, and at least one, Mot3, also acted as a prion in vivo.

“It will be hard to ignore protein-based inheritance from now on, or to consider it as an isolated exceptional case,” Chernoff wrote. “There are too many domains with proven prion properties in yeast for this to be just an accident.”

And there is no reason to believe yeast are unique in this aspect. The fact that the yeast prions could switch shape and cluster in a test tube shows that their aggregation is not directly dependent on the yeast-specific factors, Alberti said. Ghaemmaghami suggested it would be interesting to look for prions in the mammalian proteome. PrP is the only certain animal prion, although Lindquist and Eric Kandel of Columbia University in New York have reported that a protein involved in memory in the sea slug Aplysia also has prion properties (Si et al., 2003).

“I would not be surprised if there were hundreds” of prions, said Claudio Soto, who studies prions at the University of Texas Medical Branch in Houston. PrP was easy to find because of the obvious pathogenic consequences, he said, but most people in the field agree that prions are not an uncommon phenomenon.

“I think this has a lot of implications for diseases like Alzheimer’s and Parkinson’s, where we know that the key event is the misfolding and aggregation of proteins,” Soto said. Alzheimer disease can even be transmitted like a prion disease, he noted: injection of brain extracts containing amyloid-β causes pathology in recipient mice (see ARF related news story and Meyer-Luehmann et al., 2006). “There are not really a lot of differences between amyloids and prions,” Soto said.—Amber Dance.

Reference:
Alberti S, Halfmann R, King O, Kapila A, Lindquist S. A systematic survey identifies prions and illuminates sequence features of prionogenic proteins. Cell. 2009 Apr 3;137(1):146-58. Abstract