June 9, 1997 Contact: Robert Irion (408) 459-2495; firstname.lastname@example.org
RESEARCHERS DISCOVER DISORDERLY BALLS OF PROTEIN THAT MAY PROMOTE SCRAPIE, "MAD COW," ALZHEIMER'S, AND RELATED DISEASES
FOR IMMEDIATE RELEASE
SANTA CRUZ, CA--Writhing balls of snakelike protein fragments may initiate the dysfunctional lesions called plaques that clog the brains of patients with Alzheimer's disease and similar neurological disorders, according to new research at the University of California, Santa Cruz, and UC San Francisco.
Unraveling how these disorderly balls of protein promote plaque formation ultimately may help researchers develop drugs to prevent the destructive plaques that impart a Swiss-cheese appearance to the brains of mad cows, scrapie-diseased sheep, and patients with Creutzfeld-Jakob disease (CJD), Alzheimer's disease, and Parkinson's disease.
Scrapie, mad cow disease, and CJD are caused by proteins called prions ("PREE-ons") that switch between two shapes, one harmless, one harmful. Once altered, the harmful form seems contagious: It induces others to change into the dangerous version. The harmful forms aggregate together; under some conditions, they may reorder to form long chains, called fibrils, that act like sticky string. In the brain, these chains surround and kill nerve cells. Conglomerations of dead nerve cells and fibrils, similar to the plaques seen in Alzheimer's and Parkinson's patients, often accumulate in the brains of animals and people with prion diseases.
In test-tube experiments, the team discovered that a hodgepodge clot of protein fragments called "amorphous aggregate" must exist for pieces of harmless prion protein to transform into the dangerous shape. This research was the first to demonstrate that the presence of amorphous aggregate triggers the shape change.
"To understand the disease, you must understand how it forms," said Glenn Millhauser, associate professor of chemistry and biochemistry at UCSC. "If our model is right, it could suggest different strategies for drug development to halt the progress of Alzheimer's--or even prevent it."
Former UCSC graduate student Karen Lundberg and several colleagues published their research in the current issue (May 1997) of the scientific journal Chemistry & Biology. Coauthors are Chris Stenland, formerly of UCSC and now at the Bayer Corporation; biochemists Fred Cohen and Stanley Prusiner of UC San Francisco; and Millhauser.
Almost 20 years ago, Prusiner proposed the revolutionary idea that certain neurological disorders were caused by infectious proteins, which he dubbed "prions" (proteinaceous infectious particles). Unlike bacteria or viruses, prions contain no genetic material, making it hard to fathom how they could proliferate and spread disease. However, most scientists now accept the idea that prions cause mad cow disease, scrapie, kuru ("laughing cannibal" disease), fatal familial insomnia, and CJD. Some of the diseases occur spontaneously, while others are acquired through infection or inheritance.
Prion proteins are a normal but mysterious component of brains. "Your brain is loaded with this protein, and nobody knows what it does," Millhauser said. "So long as they stay in the harmless form and don't convert to the evil twin, you're in good shape." What instigates the shape change from benign to injurious is still unknown, but work in Millhauser's lab suggests a plausible model.
For her doctoral thesis, Lundberg studied a short fragment of the benign form of the scrapie-causing prion, suggested by Prusiner. She used a technique called "electron spin resonance" to watch how different solutions of the protein fragment changed over time.
The amorphous aggregate developed only when the prion protein was in high concentration. When the aggregate was present, the prion fragments switched to the dangerous shape and linked together into fibrils. Lundberg used electron microscopy to confirm the presence of those chains. However, if the amorphous aggregate was absent, the dangerous fibrils did not develop.
"The data suggest that the amorphous aggregate provides a site that induces the formation of fibrils," Millhauser said. "We are proposing a new mechanism. The amorphous aggregate may not only initiate, but also stabilize, the injurious form."
This mechanism, should it bear up under further scrutiny, poses an alternate strategy for drug therapy against diseases in which fibrils develop in the brain. Today, many researchers target the fibrils themselves by trying to cap them off and prevent them from elongating into the forms that kill nerve cells. A more fundamental approach, Millhauser hypothesizes, would be to "bust up" the amorphous aggregate in some way. "Then, fibrils would never form. That's a completely different tack, and we'd need to learn what controls the solubility of these proteins."
The National Institutes of Health and the National Science Foundation funded the research.
Editor's notes: You may reach Millhauser at email@example.com or (408) 459-2176. Mari N. Jensen, a former intern in the UCSC Public Information Office, wrote this news release.
The above post is reprinted from materials provided by University of California, Santa Cruz. Note: Materials may be edited for content and length.
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