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Yeast Protein Bolsters Prion Hypothesis

17 July 1997 7:00 pm
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Several fatal neurological diseases--including Creutzfeldt-Jakob disease (CJD) in humans and scrapie in sheep--are marked by the accumulation of protein deposits in the brain. Many researchers believe that prions or "infectious proteins" are responsible for this damage, but they have lacked solid proof. Now, in tomorrow's issue of Science,* researchers report that a protein in yeast wreaks similar havoc all by itself--at least in the test tube.

In humans and other animals, prion proteins are thought to convert from normal helixes into durable sheets, which in turn act like a template, converting other proteins. Eventually, the process would lead to accumulated masses that eventually destroy the brain. Although yeast has neither nerves nor brains, proteins in some unusual strains clump in a similar way. For instance, in the normal [psi-] strain of yeast, a protein called Sup35 is soluble, but in [PSI+] yeast cells, it forms insoluble clumps.

Molecular geneticist Michael Ter-Avanesyan and his colleagues at the Institute of Experimental Cardiology in Moscow set out to show that Sup35 alone causes the clumping. In previous work, the group had found that the protein sticks together by its tail end. To show that nothing else in the cell is responsible for the clumping, they engineered a [PSI+] yeast strain to produce extra copies of just the sticky tail end. When they purified this fragment and mixed it with normal Sup35, all of the protein changed shape and clumped together. A small piece of this clump in turn converted more normal Sup35. By the third pass, the tail-end fragment was no longer detectable, suggesting that the newly converted proteins were themselves able to convert more proteins.

The work is a huge leap forward, says biochemist Byron Caughey, who studies mammalian prions. "They have done a lot of things that we would hope to do [in mammals]," he says. But doubts will remain until someone shows that purified protein can trigger the insoluble lump in a living cell, says yeast geneticist Susan Lindquist of the University of Chicago: "That's the final nail, but that little hole is still there, and it needs to be filled in."

* For more details, Science Online subscribers can link to the full text of the Report.

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