Whitehead Institute researchers have quintupled the number of identifiable prion proteins in yeast and have further clarified the role prions play in the inheritance of both beneficial and detrimental traits.
“The big debate in the field is are the prions functional – are they evolved to be prions, or are they always a disease, as in “mad cow'” disease in mammals,” says Randal Halfmann, a graduate student in Whitehead member Susan Lindquist’s lab, and co-author of the paper featured in the April 3 issue of the journal Cell. “We wanted to find more prions and see what they’re doing, so we could answer that question.”
The Lindquist lab’s work further alters the way researchers view prions, from biological anomalies to mediators of trait inheritance and adaptations to fluctuating environments.
Prions’ bad reputation was fixed in the public’s mind by “mad cow disease.” In the late 1980s, an unidentified disease infected more than 100,000 British cattle and spread to humans, eventually killing more than 200 people. The disease causes progressive degeneration of mental abilities, which ultimately lead to death.
Scientists found the infectious agent was a prion, a misfolded version of the PrP protein found clumped together in brain cells. Brain matter in PrP-infected animals takes on a spongy appearance, lending the condition its formal name, bovine spongiform encephalopathy (BSE).
Unlike other proteins, the misfolded PrP protein is transmissible. When the misfolded PrP protein is introduced into healthy cells, it can convert normally folded PrP proteins to its misfolded shape and cause a clumping cascade characteristic of prions.
Over the years, researchers have identified other degenerative diseases caused by PrP in humans and other animals, including scrapie in sheep and goats, and variant Creutzfeldt-Jakob disease in humans. A few other prions have also been found in model organisms, such as yeast.
Believing the number of prions in yeast is higher than the four identified, researchers in Lindquist’s lab devised high-throughput methods to scan the entire yeast genome, detect probable prion-coding sequences, and confirm that the resulting proteins are in fact prions. Lindquist says, “The approach required a lot of assay development and a great deal of work but the results were very exciting.”
The bioinformatic scan located about 200 candidate prion-coding sequences in the yeast genome. The top 100 candidate proteins were tested for up to three hallmarks of prions: their tendency in cells to form clumps that remain intact when exposed to a detergent capable of unfolding most proteins; the ability of the proteins to clump in a test tube in the absence other cellular factors; and the ability of the clumps to replicate indefinitely in cells.
