Jan. 8, 1998
Vol. 17, No. 7

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    Discovery links yeast prion to 'mad cow'-type diseases

    By John Easton
    Medical Center Public Affairs

    Researchers at the University's Howard Hughes Institute have discovered that a chaperone protein from yeast, which helps proteins to change their shapes, controls a new, protein-only form of inheritance, called a yeast prion. Remarkably, the same yeast chaperone reacts with prion proteins from mammals. These prions are responsible for "mad cow" disease in cattle, scrapie in sheep, and Creutzfeld-Jakob and other fatal ailments in humans. The yeast chaperone also interacts with beta-amyloids, fibrous peptides that form the destructive tangles that are believed to cause Alzheimer's disease.

    Prions have amazed scientists with their apparent ability to cause disease by a new protein-only mechanism. When prion proteins fold into a different shape they produce indigestible tangles that can kill or damage nerve cells. This change in shape spreads to other proteins and other cells, killing the animal and producing new infectious material.

    "Although we first became aware of prions because they cause several bizarre neurological diseases, the discovery that something so awesomely similar happens in organisms as different as humans and yeast makes us suspect that there is a fundamental, common biochemical process at work here," said study director Susan Lindquist, Professor in Molecular Genetics & Cell Biology and an investigator in the Howard Hughes Medical Institute.

    "These odd diseases have focused attention on what appears to be an entirely new, gene-free mechanism of heredity that increasingly appears to be extraordinarily widespread, now that we know how and where to look," she said.

    The findings, reported in back-to-back papers in the Dec. 9 issue of the Proceedings of the National Academy of Sciences, add considerable weight to the prion hypothesis, linking the mechanism responsible for the new form of inheritance in yeast to neurodegenerative diseases of humans and animals. They provide a new target for potential therapies, and furnish a model system for more rapid and less expensive study of prion diseases and potential treatments.

    Perhaps more important, they indicate that prion-like variations in protein folding may be vastly more common than previously imagined, serving an important evolutionary role.

    The yeast protein, Hsp 104, is a chaperone, a member of a family of proteins that escort other proteins to their destinations within the cell and help them fold correctly. Hsp 104, for example, is a heat-shock protein. It protects cells from environmental stresses such as high temperatures or toxins by promoting changes in shape in stress-damaged proteins, restoring them to their working forms.

    Lindquist's team also found that a chaperone protein from bacteria (GroEL) can interact with prion proteins. Again, this points to universal biochemical mechanisms being at work.

    Mounting evidence has linked Hsp 104 to a role in regulating whether the yeast prion folds into its normal working or abnormal non-functional conformation. This study provides the first direct evidence of the Hsp 104-prion interaction.

    The real surprise, however, was the powerful affinity between the yeast and bacterial chaperones and the mammalian prion. The primary structure of the mammalian prion protein is completely different from that of the yeast prion protein. But they both have a very unusual ability to change shape and to spread this change in shape from cell to cell. Unlike mad-cow prions, the yeast prion doesn't kill cells, but it does alter their appearance and activity.

    Chaperones are ordinarily extremely specific, interacting only with proteins that have particular types of structures. Neither Hsp 104 or GroEL interacted with any of the dozens of other proteins tested, but each produced an effect on both yeast and mammalian prion proteins.

    "The yeast and the mammalian prion proteins are genetically, structurally and functionally entirely different," said Lindquist. Except for the fact that they can both change shape and form large protein tangles, scientists hadn't detected any significant similarities between them. "But these chaperones are telling us that, although we haven't found it yet, there is a remarkable underlying biochemical resemblance."

    This mysterious likeness of proteins among cows and sheep, humans, and yeast strongly suggests that prions may play an essential evolutionary role, allowing organisms with identical genes to adapt under stress to different environments and to transmit that survival advantage to their neighbors and progeny.

    "This provides the first plausible molecular mechanism for a cell to respond to its environment with a heritable change in phenotype," Lindquist said.

    In addition to Lindquist, the research team includes Eric Schirmer, a graduate student in Lindquist's lab; Shubhik DebBurman, a post-doctoral fellow in the lab; and Gregory Raymond and Byron Caughey of the Laboratory of Persistent Viral Diseases, NIH/NIAID Rocky Mountain Laboratories, Hamilton, Mont.

    The research was supported by grants from the National Institutes of Health and the Howard Hughes Medical Institute.