May 7, 1996

Contact: Amy Adams or Robert Irion (408) 459-2495; irion@ua.ucsc.edu

UC SANTA CRUZ RESEARCHERS STUDY PROTEIN CLUMPS THAT MAY CAUSE "MAD COW" AND RELATED DISEASES

FOR IMMEDIATE RELEASE

SANTA CRUZ, CA--Mad cows, laughing cannibals, itchy sheep, and ten new cases of a rare human brain disorder called Creutzfeldt-Jakob disease (CJD) in Great Britain are all part of a puzzle that has scientists stymied. In these diseases, as well as other neurological disorders such as Alzheimer's and Parkinson's diseases, dense plaques of misfolded proteins mysteriously clog up the brain.

How proteins fold and unfold--and what happens when the folding goes haywire--are questions of interest to biochemists Anthony Fink, Lydia Gregoret, and Glenn Millhauser at the University of California, Santa Cruz. Their research focuses on different aspects of protein folding, such as what controls the final shapes of proteins, how they clump into damaging plaques, and how to prevent those plaques from forming.

Some of their work focuses on a band of renegade proteins called prions (PREE-ons), the alleged cause of mad cow and related diseases. Unlike either bacteria or viruses, prions contain no genetic material; they are the only protein thought to transmit disease. All prion diseases cause neurological problems and inevitably lead to death. The diseases include sheep scrapie and three human disorders: CJD, Fatal Familial Insomnia, and Kuru--called the "laughing death" by New Guinea cannibals, who appeared to get the disease from ritually eating human brains.

"The chances of someone getting these diseases are clearly pretty low," says Fink. Even so, the UCSC studies could help scientists understand the basic workings of these and other more common neurodegenerative diseases.

Prions are harmless in their normal state. Shaped like folded slinkies, they dot the outside of neurons, serving an unknown, but probably useful, function. On rare occasions they may unwind and refold into rippled sheets. These misfolded prions initiate a domino- like cascade of prion refolding until the entire brain teems with dangerously crinkled prions.

The first misfolded prions may arise from a mutation, but they can also be ingested. Prions are unusual in being able to survive the burbling acidic soup of the stomach. Not only this, but they also appear to trek up to the brain, overcome the blood-brain barrier, then march into the unsuspecting gray matter. Prion-diseased brains then become riddled with a network of spongy holes and contain dense plaques where misfolded prions have clumped together.

Despite some skepticism about whether prions can accomplish these feats of protein migration, most scientists believe that feeding parts of infected sheep to cattle is what kicked off the mad- cow epidemic in Great Britain. Some scientists also believe the ten new CJD cases may have resulted from people eating infected beef. However, Fink says, "The evidence that people picked up this disease from eating beef is highly speculative."

Prion clumps in diseased brains form into long fibers, as if each misformed prion reaches out to hold hands with the one next door. Glenn Millhauser, an associate professor of chemistry and biochemistry, studies how these prion chains arise. With researchers at UC San Francisco, Millhauser's group--including graduate student Karen Lundberg and postdoctoral researcher Chris Stenland--devised a way to monitor prion fragments as they metamorphose from their proper springlike coils into long strands of misfolded prions.

This work has begun to answer questions about the genesis of prion chains. In the past, scientists were unsure whether prions crystallize into their alternate form, or if individual misfolded prions actively convert their neighbors. Results from Millhauser's lab support the first model. Misfolded prions seem to act as seed crystals, initiating a wave of crystallization into the damaging rippled shape.

The shape so dangerous in prions is actually a common protein form, taken on as part of the normal healthy function of some proteins. Assistant professor of biology Lydia Gregoret worked with computer scientist David Haussler, graduate student Melissa Cline, and undergraduate Albion Baucom to create a computer program that predicts which proteins will fold into this shape, called a beta- pleated sheet.

"Normal proteins fold and unfold all the time with no harmful consequences," says Gregoret, but most of them eventually assume one preferred shape. Prions are unusual in their ability to switch from a coil to a pleated sheet, and especially unusual in their obstinate refusal to switch back.

Fink, a professor of chemistry and biochemistry, studies another coiled protein that occasionally gets stuck in the pleated sheet form. This protein seems to form aggregates when partially folded proteins interact and induce each other to form stable pleated sheets. Fink is trying to find ways of stopping prions and other pleated-sheet aggregates from forming by preventing the proteins from ever grabbing hold of each other. He is looking for small molecules that will give proteins something to latch onto besides each other, thwarting any attempts to form chains.

This release is also available on the World Wide Web at UCSC's "Services for Journalists" site (http://www.ucsc.edu/news/journalist.html) or via modem from UC News Wire (209/244-6971).

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