CAMBRIDGE, Mass. (May 20, 2004) – Amyloid fibers, those clumps of plaque-like proteins that clog up the brains of Alzheimer’s patients, have perplexed scientists with their robust structures. In laboratory experiments, they are able to withstand extreme heat and cold and powerful detergents that cripple most other proteins. The fibers are in fact so tough that researchers now are exploring ways that they can be used in nanoscale industrial applications. While they are not necessarily the cause of Alzheimer’s, they are associated with it and with many other neurological conditions, and researchers don’t yet have a way to assail these resilient molecules.
A study published this week in the advance online publication of the journal Science suggests that yeast may succeed where scientists have not. The research by a team at Whitehead Institute for Biomedical Research reports on a natural biological process by which yeast cells dismantle amyloid fibers.
“These proteins are remarkably stable,” says Susan Lindquist, director of Whitehead and lead researcher on the project. “This is the first time that anyone has found anything that can catalytically take apart an amyloid fiber.”
The finding follows years of study that has focused on a yeast protein called Sup35, a protein that helps cells translate genetic information into strings of amino acids – the building blocks of protein molecules. Sometimes Sup35 suddenly forms amyloid fibers similar to those found in Alzheimer’s patients. In yeast, however, this doesn’t kill the cell. Rather, it is part of the cell’s normal biology, changing the types of proteins that the cell makes – changes that can sometimes be beneficial.
Previous research in the Lindquist lab described how a protein called Hsp104 seemed to affect Sup35’s ability to form amyloid fibers. When a yeast cell contained either high amounts of Hsp104 or none at all, amyloid fibers never formed. But when Hsp104 levels were small, the fibers flourished.
While these types of relationships between chemicals aren’t unheard of, “it was counter-intuitive. Both high levels of Hsp104 and the absence of Hsp104 caused the same effect. That certainly made us want to figure out what was going on,” says Lindquist, who is also a professor of biology at MIT. “It was hard to come up with a definitive experiment in a living cell that would explain this sort of thing.”
In this new study, Lindquist and postdoctoral researcher James Shorter isolated Sup35 and Hsp104. Here they saw that small amounts of Hsp104 catalyzed the formation of amyloid fibers, but large levels of the protein actually caused the fibers to dissolve.
“Given their resilient structure, the fact that a protein can take apart these amyloids is remarkable,” says Lindquist. “It has huge implications for our understanding of the protein folding process in amyloid-related conditions.”
This research also may contribute to scientists’ understanding of evolution. Prions, those infectious proteins implicated in conditions such as mad cow disease, are a subclass of amyloids. In yeast cells, Sup35 technically is a prion, although it is not toxic to the cell. Many researchers suspect that because prions have been so well conserved in yeast for hundreds of thousands of years, they must serve some sort of evolutionary purpose – and that’s where Hsp104 comes in.
Hsp104 belongs to a class of proteins that sometimes are influenced by environmental factors. It is conceivable, Shorter explains, that a yeast cell in one type of environment can experience an abundance of Hsp104, which would then keep Sup35 from forming amyloid fibers in that cell. But put that cell in a different environment and the result may be a more moderate level of Hsp104 that would, in turn, create amyloid fibers in Sup35, changing how that protein functions and ultimately altering the cell’s biology. And because these changes could then be passed on to subsequent generations of cells, this, the scientists note, would be an example of environment guiding the evolutionary process.
“This is speculation that hasn’t been demonstrated yet,” says Shorter. “For obvious reasons it’s hard to prove any evolutionary argument. But this paper is one indication that this might be the case.”
Written by David Cameron.
Full citation for print versions
© Science, early online e-edition, May 20, 2004
“Hsp104 Catalyzes Formation and Elimination of Self-Replicating Sup35 Prion Conformers”
Authors: James Shorter and Susan Lindquist.
Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA
This work was supported by a Charles A. Kind Trust post-doctoral fellowship and the National Institutes of Health.
Whitehead Institute for Biomedical Research is a nonprofit, independent research and educational institution. Wholly independent in its governance, finances and research programs, Whitehead shares a close affiliation with the Massachusetts Institute of Technology through its faculty, who hold joint MIT appointments.
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