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Destructive protein can also help cells survive tough times

Prions

Prions

Image by Kateryna_Kon. Photo courtesy of Zachary Harvey.
May 4 2020
Patricia Waldron
 

Prions usually make the headlines for causing illness and death, such as mad cow disease in cattle or chronic wasting disease in deer. But a growing body of research suggests that these tiny proteins have a helpful side too -- and they might be due for a rebranding. 

Prions are misshapen proteins that rapidly convert other proteins into the same configuration, changing their function and creating clumps called aggregates. When first identified, prions were known as agents of disease. But in the past two decades, scientists have uncovered multiple beneficial roles for prions, as well.

Stanford biochemist Daniel Jarosz, PhD, is using Saccharomyces cerevisiae -- a yeast useful for making beer, bread and molecular discoveries -- to investigate how prions help cells during hard times and pass those changes down to the next generation.

"It turns out that many prions can help yeast adapt to more stressful environments and do all kinds of really interesting things," said Jarosz, an associate professor of chemical and systems biology and of developmental biology.

Graduate student Zachary Harvey in the lab of Stanford biochemist Daniel Jarosz.

In previous work, researchers in Jarosz's lab identified a prion that enables yeast cells to communicate with bacteria. This helps yeast cells know whether to gobble up glucose or to take their time dining on a larger variety of sugars. Another prion they found helps cells decide between two survival strategies: reproducing as usual or turning into a spore and going dormant during food shortages.

Other researchers have found that prions are necessary for forming long-term memories, at least in sea slugs and fruit flies. The human versions of these same proteins also have the potential to convert into prions, but human studies are just beginning.

In a new paper in Cell, senior author Jarosz discussed a discovery by researchers in his lab of a prion in yeast that acts like a molecular panic button, activating a whole slew of genes that help yeast survive stressful times. 

Zachary Harvey, a graduate student in Jarosz's lab and the lead author on the paper, discovered that the protein, called Snt1, normally blocks stress genes from being expressed. When in its prion form, Snt1 does the opposite: It turns on inactive parts of the genome. 

Some of these changes make yeast immune to drugs commonly prescribed to treat fungal infections, he found. When yeasts divide, their offspring inherit the prion, and because the same parts of the genome are still activated, the cells are also immune to the drugs.

When Harvey initially proposed that prions could activate silent parts of the genome in a heritable way, Jarosz was skeptical. "I thought it was really provocative idea, but countered that there was not one shred of evidence to support it," said Jarosz, who received a Stanford Medicine Discovery Innovation Award to study the finding. 

The discovery of Snt1's function as a prion may explain why disease-causing fungi become resistant to antifungal drugs so easily, said Jarosz:  

There are far fewer drugs available to treat fungal pathogens than bacterial infections, and many have significant side effects or can't be given in an outpatient setting. Unfortunately, resistance arises prodigiously and has been recognized by the U.S. Centers for Disease Control and Prevention as an urgent health threat.

Additionally, Jarosz said that understanding why one type of prion causes disease, while another is helpful, could lead to innovative treatments for diseases that involve similar clusters of proteins, such as Alzheimer's and Parkinson's disease. 

"You can make aggregates of different proteins in cells, and some of them clearly stress the cells a great deal. Others of them are entirely benign or even have beneficial consequences," said Jarosz. "Understanding that difference in terms of molecular features of the aggregates -- and also how our cells respond to them -- is very important as our population ages."