Formation of the notorious protein aggregates might protect cells from stress, study suggests
Feb 1, 2017 | Atlanta
Prions are notorious for causing devastating neurodegenerative diseases, such as mad cow disease. How these infectious self-perpetuating protein aggregates propagate—by getting other protein molecules of the same sequence to join the pile—is hands down insidious.
Yet prion formation could represent a protective response to stress, according to research from Emory University School of Medicine, Georgia Tech School of Biological Sciences, and St. Petersburg State University, in Russia. The results were published in the Jan. 17, 2017, issue of Cell Reports.
The scientists show that the yeast protein called Lsb2 forms a “metastable” prion in response to high temperature. The Lsb2 prion can persist for a number generations after the heat stress and can convert other proteins into prions, says Yury O. Chernoff, a professor in the Georgia Tech School of Biological Sciences.
Because high temperature causes proteins to misfold, the scientists propose, prion formation could be an attempt by cells to impose order upon a chaotic jumble of misfolded proteins, which would harm the cell. If so, the prion forms are protective—even if as the “lesser of two evils,” as Chernoff puts it—and prion formation under heat stress could be an adaptive response.
“It’s fascinating that stress triggers a cascade of prion-like changes in Lsb2 and that a memory of stress may persist for a number of cell generations,” Chernoff says. “It would be interesting to see whether other proteins can respond to environmental stresses in the same way the Lsb2 does.”
"What we found suggests that Lsb2 could be the regulator of a broader prion-forming response to stress," Wilkinson says.
Other investigators studying yeast prions have been finding examples of how they may help cells adapt to a changing environment. The new findings are consistent with this idea, Chernova says. Moreover, the evolutionary history of the yeast genome indicates that increased heat tolerance coincides with an amino acid substitution that enables Lsb2 to transform into a prion.
Understanding how and why prions form could illuminate Alzheimer’s disease research, because the behavior of the toxic protein fragment beta-amyloid, central in Alzheimer’s, strongly resembles some features of prions. The Cell Reports authors note that the yeast protein Lsb2 has some sequence similarity to a human protein called Grb2, known to interact with APP, the precursor of amyloid-beta.
This research was supported by the National Institutes of Health (GM093294), the National Science Foundation (MCB 1516872), and the Russian Science Foundation (RSF 14-50-00069).