Posted July 29, 2011 Atlanta, GA
Georgia Tech College of Sciences
It’s a chicken and egg question. Where do the infectious protein particles called prions come from? Essentially clumps of misfolded proteins, prions cause neurodegenerative disorders, such as mad cow/Creutzfeldt-Jakob disease, in humans and animals. Research in fungi has suggested that sometimes prions can also help cells adapt to different conditions. Prions trigger the misfolding and aggregation of their properly folded protein counterparts, but they usually need some kind of “seed” to get started.
Scientists have studied a yeast protein called Lsb2 that can promote spontaneous prion formation. This unstable, short-lived protein is strongly induced by cellular stresses such as heat. Lsb2’s properties also illustrate how cells have developed ways to control and regulate prion formation. The results are published in the July 22 issue of the journal Molecular Cell.
The study was conducted by members of the Center for Nanobiology of the Macromolecular Assembly Disorders (NanoMAD) which is made up of scientists from the Georgia Institute of Technology and Emory University. Scientists from the National Institues of Health and the University of Illinois at Chicago also contributed to the study. The first author is senior associate Tatiana Chernova, PhD at Emory.
The aggregated, or amyloid, forms of proteins connected with several other neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s can, in some circumstances, act like prions. So the findings provide insight into how the ways that cells deal with stress might lead to poisonous protein aggregation in human diseases.
“A direct human homolog of Lsb2 doesn’t exist, but there may be a protein that performs the same function,” said Keith Wilkinson, professor of biochemistry at Emory University School of Medicine. “The mechanism may say more about other types of protein aggregates than about classical prions in humans. This mechanism of seeding and growth may be more important for aggregate formation in diseases such as Huntington’s.”
Lsb2 does not appear to form stable prions by itself. Rather, it seems to bind to and encourage the aggregation of another protein, Sup35, which does form prions.
“Our model is that stress induces high levels of Lsb2, which allows the accumulation of misfolded prion proteins,” Wilkinson said. “Lsb2 protects enough of these newborn prion particles from the quality control machinery for a few of them to get out.”
In continuation of previous research by Yury Chernoff, director of NanoMAD and professor in the School of Biology at Georgia Tech, the new data also show that in addition to promoting new prions, Lsb2 strengthens existing prions during stress.
"Little is known about physiological and environmental conditions influencing amyloid diseases in humans," said Chernoff. "Therefore, prophylactic measures, which could end up being more effective than therapies, are essentially non-existant. We hope that yeast model will help to fill this gap."
The research was supported by the National Institutes of Health.
Written by: Emory University and the Georgia Institute of Technology