COULD THE ROLE OF PRIONS EXTEND TO ALZHEIMER'S DISEASE—AND BEYOND?

SEATTLE—A series of compounds now being tested in animals and in vitro assays may offer a therapeutic approach for treating human prion diseases, Stanley Prusiner, MD, said at the 124th Annual Meeting of the American Neurological Association. Prions—proteinaceous infectious particles that lack nucleic acid—are most familiar as the pathogenic agents in Creutzfeld-Jakob disease in humans and scrapie in sheep. However, Dr. Prusiner suggested that they may also play a role in more common neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. If the new compounds prove successful in treating Creutzfeld-Jakob disease and related conditions, they may provide a blueprint for intervention in these other diseases as well.

"This is only just beginning," said Dr. Prusiner, who is Professor of Neurology, Biochemistry and Physics at the University of California, San Francisco. "There are thousands of compounds available that have been made over the past 10 years" that might interrupt prion synthesis.

While new variant Creutzfeld-Jakob disease, or "mad cow" disease, is in the spotlight at the moment, "I think the major impact of these discoveries by far will be their importance for all neurodegenerative diseases, whether they are in the brain or outside the brain," Dr. Prusiner said at a news conference.

Human prion diseases may be genetic, as in 10% to 15% of cases of Gerstmann-StrSussler-Scheinker disease, or they can be sporadic or infectious, as in Creutzfeld-Jakob disease. New variant Creutzfeld-Jakob disease has now been diagnosed in 50 individuals—48 in England, one in Ireland, and one in France. Although Dr. Prusiner believes that the "mad cow" epidemic has peaked, other experts disagree on how many more people will ultimately be affected, "with estimates running from hundreds to 100,000." Creutzfeld-Jakob disease has also been transmitted iatrogenically.

Research over the past 25 years by Dr. Prusiner and others has made great strides in determining the structure of both the normal, cellular prion protein, PrPC, and the infectious, pathogenic variety, PrPSc. Transgenetic studies, Dr. Prusiner noted, suggest that "PrPSc acts as a template upon which [molecules of] PrPC refold into a nascent PrPSc molecule through a process facilitated by another [thus far unidentified] protein," termed protein X. During prion propagation, protein X appears to bind to the terminus of the normal protein structure, which has a high alpha helical content, but not to the abnormal scrapie form, which "acquires a substantial beta sheet content post-translationally."

The conversion from normal to pathogenic form, Dr. Prusiner said, occurs in caveolae-like domains near the cell surface, although the details remain unclear. "In the prion diseases, we know there's a feedback mechanism. The abnormal form of the protein, the one with the beta sheet content, somehow feeds back, but we don't understand the feedback mechanism."

While the transformation into abnormal proteins may be triggered by exogenous PrPSc, in the case of inherited diseases the trigger is a mutant form of the prion protein that is prone to flipping into the scrapie conformation even without a template. "A cell could probably handle one or two molecules of PrPSc, but if enough of them flip—or if the cell happens to become slightly more alkaline or acid, or slightly hypoxic or hyperoxic—that could be a trigger for more of them to flip," eventually leading to disease, Dr. Prusiner said.

This same pathogenic cascade, he suggested, may also operate in other neurodegenerative diseases, such as Alzheimer's disease. "I don't know what the trigger is, but there has got to be some driving force that keeps propelling the misfolding and misprocessing of proteins so that you end up with plaques and tangles." Similarly, the process might be responsible for the misfolded Lewy bodies seen in Parkinson's disease, and the long fibrils of tau that occur in frontotemporal dementia.

Dr. Prusiner, who met with widespread skepticism when he originally proposed that a proteinaceous particle without nucleic acid could transmit disease, was later awarded the Nobel prize for his research into prions. Now, he said, he expects his ideas about the relationship of prion diseases to more common neurodegenerative conditions to spark significant controversy as well.

Nevertheless, he noted that the putative link between infectious prions and neurodegenerative diseases, if confirmed, offers novel opportunities for intervention. "Striking epidemiologic, clinical, pathologic, and genetic similarities among Alzheimer's disease, Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis, and prion diseases" suggest that prion research could lead to new treatments, or perhaps preventive measures, for these diseases, he said.

One potentially valuable approach is to focus on the various steps of prion conversion. "Our goal," Dr. Prusiner said, "is to interrupt this change from the normal protein into the abnormal, modified version." For example, during conversion, protein X appears to bind to a stable, intermediate form of PrPC that has not yet attained the pathogenic conformation; drugs that bind to PrPC at this step may prevent conformational change from occurring and thus halt the disease.

By searching through a databank of 210,000 molecules whose structures are known or suspected, Dr. Prusiner and colleagues recently identified 63 commercially available compounds that had an epitope that could bind to PrPC. Three of these compounds proved to inhibit conversion in experimental assays, yet were not cytotoxic, and one of them, a pyridine that Dr. Prusiner referred to as "compound 60," has shown particular promise. He and his colleagues have been working to create molecular analogs that might bind even more effectively; and these drugs, which "present a very exciting new approach," are being tested in animal models, according to Dr. Prusiner.

Returning to the more familiar prion diseases, Dr. Prusiner noted that because of the publicity generated by new variant Creutzfeld-Jakob disease, surveillance for all prion diseases has increased, especially in Europe. He believes there is little danger of "mad cow" disease becoming a problem in the United States, although a University of Wisconsin report indicated that a prion disease was passed to a mink from a "downer" cow—a sporadic, infected animal that fell down and died, and whose flesh was subsequently fed to the mink.

Most cows in the United States are range-fed and do not get bone meal supplements of the sort that facilitated the spread of prion disease in Britain. However, it is theoretically possible that pigs could get the disease, and chickens have a PrP gene as well, Dr. Prusiner noted. "But," he added, "I don't know how we'd tell a demented chicken."

—Jean McCann
Contributing Writer

Suggested Reading
Prusiner SB. Prions. Proc Natl Acad Sci. 1998;95:13,363-13,383.