Amyloid -Dissolving Protein May Be Alzheimer Breakthrough

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.”