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Stetten Lecturer Sheds Light On Prion Hypothesis

By Alison Davis

Whimsically entitled "Mad Cows Meet Psi-Chotic Yeast: The Expansion of the Prion Hypothesis," this year's DeWitt Stetten, Jr. Lecture will feature Dr. Susan L. Lindquist of the University of Chicago. She will tell how her work on stress-triggered heat-shock, or chaperone, proteins has helped unravel a decades-old genetic mystery: the identity of an unconventional, inherited genetic element in yeast cells called [PSI+]. The talk, sponsored by NIGMS, will be held on Wednesday, Oct. 21 at 3 p.m. in Masur Auditorium, Bldg. 10.

Dr. Susan L. Lindquist

Since she was a graduate student, Lindquist, now a professor of molecular genetics and cell biology, has been interested in how cells react to stressful situations such as exposure to heat or noxious chemicals. A key mechanism cells have evolved over time to cope with such stresses is the production of a set of protective proteins called heat-shock proteins, or chaperones. As the name implies, chaperones prevent inappropriate interactions between other cellular proteins while also helping them to fold both properly and efficiently. Over the years, Lindquist's studies have clarified the myriad roles chaperones play in the cell. Only recently has her research ventured into the burgeoning new field of prions. In fact, according to Lindquist, her work on yeast prions came about
"by sheer accident."

A few years ago, she got a call from a colleague, Dr. Yury Chernoff of the University of Illinois at Chicago. Chernoff, in the course of his studies of the [PSI+] element in yeast, stumbled upon one of the chaperones, Hsp104, that Lindquist's group had been researching. As it turns out, Hsp104 somehow interacts with the protein encoded by the yeast [PSI+] gene, called Sup35. Sup35, it happens, is a microbial analogue of prions, the protein culprits that are intimately involved with the devastating neurological ailment Creutzfeldt-Jakob disease in people and its correlate in cows, "mad-cow disease."

Worldwide interest in prions was heightened last year when Dr. Stanley Prusiner of the University of California, San Francisco, netted the Nobel Prize in physiology or medicine for his two decades of work on prion particles -- what the Nobel committee described as a "new genre of diseasecausing agents."

Lindquist's work on yeast chaperones like Hsp104 has introduced a whole new role for these proteins in coaxing prion-like proteins such as Sup35 to aggregate into clumps and stringy fibers. What's more, her work may eventually point the way to new therapeutic targets by offering scientists a simple model system in which to study prion-related diseases and potential therapies. In yeast, for instance, Lindquist has found that titrating the level of chaperones in the cell can actually "cure" affected cells.

In addition, she said, protein folding studies are exceedingly difficult to perform in the cells of higher organisms. She hopes that the yeast system will provide a simpler way to investigate prions. "We can screen yeast cells much more easily, cheaply and quickly than mice," Lindquist said.

Prions are thought to act through a highly unusual mechanism in which a few misshapen prion molecules jostle normal proteins in the same cell and get them to assume the same deformed shape. Lindquist's work has shown that, at least in yeast, the chaperone Hsp104 somehow participates in this chain reaction. The process is unusual in that it is self-perpetuating and it can be passed from one generation to the next without ever involving a nucleic acid.

In mammalian cells, clumps of prions coalesce into knotty tangles, harming brain cells and leading to the spongiform encephalopathies such as Creutzfeldt-Jakob disease and sheep scrapie. In yeast cells, however, the situation isn't so dire, Lindquist said. While the condition may not be entirely harmless, yeast cells can survive with an abundance of prions, she said. In fact, Lindquist and her group have devised a clever way to spot prion-"infected" yeast cells by attaching a glowing green tag to the Sup35 protein and then visually screening cells for signs of clumping.

Lindquist is excited by the remarkable biochemical similarities between yeast and mammalian prions, but she is even more fascinated by yeast prions' ability to serve as a mechanism of inheritance. Prion-containing cells have physiologies distinct from normal cells, and such differences are inherited by a "protein-only" mechanism: heritable changes in protein structure. "This might be a very ancient mechanism in which information is transmitted from one generation to the next," Lindquist said. "We want to know how it works and how broadly it applies."

NIGMS has supported Lindquist's work since 1978.


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