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Susan Lindquist and colleagues have collaborated to show that proteins involved in normal cell processes can convert to a self-perpetuating, prion-like form to maintain memory, for example.
Si is working on the Aplysia CPEB homolog in the fruit fly and is using the model system to probe the role of prion-like features in learning and memory. Kandel's lab group has found a homolog of Aplysia and fly CPEB in mice. A homolog of CPEB also exists in humans.
Most prion studies have been in the fast-growing yeast Saccharomyces cerevisiae, which yielded the first clues to the potential benefits of some prions. In 1994, Reed Wickner of the National Institutes of Health reported that certain yeast proteins could exist in a normal form and a misfolded prion form. A case in point, the protein known as Sup35p can switch back and forth between a normal and a prion version—PSI+ and psi-. The PSI+ form is self-replicating and forms fibrous amyloids, just as in mammals.
Lindquist entered the field around the time that Wickner published his landmark observations. She was working on a “heat-shock” protein, Hsp104, which, she showed in a 1998 paper, helps yeast adapt to changes in temperature by dissolving aggregated proteins. She and others observed that Hsp104 plays an essential role in the maintenance of yeast prions.
“Later, my lab reported that PSI+ was an ‘evolvability factor’ that had a beneficial effect in allowing cells to try out genetic variation hidden in their genome,” Lindquist says.
“When the proteins switch into the prion state, their function is switched,” Lindquist explains. “They change the pattern of gene expression in the cell, and we think that this provides immediate new biological states that are potentially beneficial and could help the organism to evolve more quickly.”
When the yeast is suddenly confronted with changing conditions, says Lindquist, the organism doesn't switch the whole colony to prions. Just a small number of cells make the conversion—turning on previously silent genes to test the waters, so to speak. “We think of this as a ‘bet-hedging’ strategy,” she explains. The more stress the yeast is under, the more likely its proteins will misfold and become prions—“like gamblers who put money on more numbers on a roulette wheel.”
For example, Lindquist explains, if a grape dusted with yeast falls from the vine and into a puddle, the yeast is now in a drastically different environment. Various prions in the water-logged yeast cells will switch from inactive to active, or active to inactive, to ensure that some of the cells survive underwater. Some of those activation switches help the yeast, but some do not.
Jonathan Weissman, an HHMI investigator at UCSF, has studied survival functions of the PSI+ prion independently and also in collaboration with Lindquist. He agrees that, while the PrPSc is almost certainly toxic, “that doesn't mean that other proteins can't form prions that are beneficial,”—especially because, as he has shown, they have been conserved in microorganisms for hundreds of thousands of years.
Lindquist and colleagues reported in Cell in 2009 that they had surveyed the yeast genome and uncovered 19 proteins that have prion states. The collection of new phenotypes that can be selected by prion switching potentially helps the yeast adapt to environmental variables such as salt concentration, oxidative stress, and changes in carbon sources.
Photo: Cheryl Senter / AP ©HHMI
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