Yeast Protein Supports Prion Theory

Researchers may have learned how a yeast protein usurps the usual role of DNA: transmitting a trait from one generation to the next. A few molecules of the protein, they found, can trigger the formation of long protein fibers similar to those in the brains of patients with neurological disorders such as Creutzfeld-Jakob disease. The finding, reported in today's issue of the journal Cell, not only sheds light on this odd form of inheritance, but also lends support to a controversial theory about how such fibers may develop in human diseases.

The team of researchers, led by yeast cell biologist Susan Lindquist of the University of Chicago, had demonstrated last year that a metabolic trait in yeast called [PSI+] could be passed from one generation to the next without changes in the yeast's DNA. The protein that seems to be responsible, called Sup35, usually helps cells translate its genes into proteins. In abnormal [PSI+] cells, which are genetically identical to normal cells, the important protein clumps together, and the cells are unable to grow under certain conditions. Lindquist's group theorized that the trait is passed from one generation of cells to the next by a misfolded protein that triggers other proteins to change their shape as well.

To determine if Sup35 could change shape on its own or if it needed help from other molecules in the cell, the team studied the purified protein in the test tube. They found that although the protein stayed soluble for a week or two, it eventually polymerized into long fibers resembling those in so-called prion diseases--brain diseases such as scrapie in sheep, "mad cow disease" in cattle, and Creutzfeldt-Jakob disease in humans. The researchers also found that if they added even a tiny amount of the polymerized protein to a solution of purified Sup35 as a "seed," the entire solution polymerized more quickly.

The researchers propose that the [PSI+] switch happens when a Sup35 protein folds incorrectly and then starts to form a chain with others of its kind. Lindquist says the theory "provides such a simple mechanism" for the odd genetics that "it's pretty convincing." Peter Lansbury of the Center for Neurological Disease at Brigham and Women's Hospital in Boston agrees, and says the work lends credence to the theory that misfolded proteins, or prions, cause the fibers in diseased brains. He cautions, however, that Sup35 is very different from the proteins involved in mad cow and Creutzfeldt-Jakob diseases. The new results may "get people to look carefully at the [prion] idea," he says, "but still the experiment needs to be done with the prion protein."

Posted in Biology