Prions linked to nerve regulation.

Prions Linked to Nerve Regulation

Scientists probing the highly specialized juntions between the nerve cells and muscles have stumbled upon a biological coincidence that may reveal the bases of several mysterious brain diseases.

The researchers, led by Gerald D. Fischbach of the Washington University School of Medicine in St. Louis, initially sought to investigate a nerve-secreted protein that regulates the interaction between nerves and muscles.

What the research led to, however, was an unplanned journey into the world of "prions" -- proteins implicated in several neurodegenerative diseases with names that Fischbach is still learning to spell, such as Creutzfeldt-Jakob disease and Gerstmann-Strassler syndrome. "I am not the world's expert in these things," Fischbach sighs, caught in a flurry of questions about his newly inherited field of study. "I'm trying to read about them now, for sure."

Researchers have found prions in normal brain tissue of humans and other mammals, but they have yet to learn the role of these proteins. In a slightly mutated form, prions appear to either trigger or exacerbate certain neural diseases whose primary infectious agents remain unidentified. These include scrapie, a brain disease in sheep, and several diseases in humans.

For Fischbach, Douglas L. Falls, David A. Harris and their co-workers, the link between receptor regulation and prions first appeared on a computer printout. The researchers had spent years purifying a protein that triggers production of a receptor on chicken muscle fibers. Once the muscle fibers sprout these receptors, they become sensitive to subsequent chemical signals transmitted by the nerves. When the scientists entered into a computer their protein's animo acid sequence, the computer informed them it had seen some similar sequences before. Indeed, roughtly one-third of their protein had stretches identical to those of prion proteins. Moreover, with the exception of only one amino acid, a 24-amino-acid length of their receptor-inducing protein was identical to a segment common in prions -- a remarkable coincidence considering the proteins had been isolated from entirely different species. A high degree of sequence similarity generally indicates proteins have identical or very similar functions.

The finding strongly suggests that a prion's normal role is to regulate production of neurochemical receptors in the nervous system, Fischbach told colleagues last week at the annual meeting of the Society for Neuroscience in Phoenix, Ariz. Moreover, it provides an attractive explanation for how mutant prions might trigger neurodegenerative diseases. If receptor production becomes disrupted by faulty prions, Fischbach speculates, nerves would have trouble getting their messages transmitted. And previous work has shown that when nerves can no longer communicate with surrounding cells, they degenerate and die.

"It's exciting and startling. Everyone you tell it to can't believe it at first," says Zach W. Hall, a neuroscientist at the University of California, San Francisco. "It is one of those things that molecular biology does for us so often these days: to suddenly and dramatically bring together two completely unrelated areas of research. I don't think anyone would have dreamed of this similarly without the help of a data bank to tell you that these proteins are related."

Many questions about prions and neuroreceptors remain, Hall says. "But it means we can think about each of these problems in new ways. It'll suggest new experiments on both sides."