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Beware the Shape-shifter:
The trouble with proteins

by Alicia P. Gregory

But how do good proteins go bad? The prion protein, PrP for short, can somehow transfigure itself into a pathogen simply by changing shape. As PrP twists, bends and folds, it undergoes a transformation akin to Dr. Jekyll and Mr. Hyde.

The good and evil versions are chemically identical chains of more than 200 amino acids. The only difference in the evil protein—the one that can cause disease—is misfolded sections that take on a flat shape rather than the normal spiral. The rogue, misshapen protein then has the ability to warp other pure proteins into disease-causing shapes, which, in turn, lock together forming long chains that kill nerve cells, riddling brain tissue with holes.

Prions are an entirely different breed of evil. Coined by Stanley Prusiner in the early 1980s, and derived from "proteinaceous infectious particle," the term "prion" marked a new paradigm of infection. Up to that point every infectious agent known to science fell into the well-defined categories of virus, bacteria, fungi, or parasite, and certainly anything infectious had to have a genetic component (some DNA or RNA) to drive it. Proteins couldn't be infectious on their own—or could they?

Placing the blame
"Looks like a virus, smells like a virus, must be a virus." Telling says this was the obvious conclusion for scientists searching for a causative agent in scrapie.

But Prusiner set out to test a sensational theory that the infectious agent lacked any nucleic acid (DNA or RNA). His work at the University of California-San Francisco revealed that the prion protein could fold into two distinct shapes (what scientists call conformations)—one normal (PrPc: the amicable Dr. Jekyll) and one that caused scrapie (PrPSc: the nefarious Mr. Hyde).

"He was the first to show that to cause disease this protein somehow goes awry, and it appears this happens when it shape-shifts," says Telling, who worked with Prusiner for eight years in San Francisco, first as a postdoc and later as a faculty member.

Telling says Prusiner was regarded as a maverick at the time he proposed his prion theory. "He had trouble getting funding from NIH, and his views were not widely accepted. Since then, Stan has done a remarkable job to convince people, by doing excellent science and rallying the aid of a lot of very smart people." Prusiner's work was further vindicated with the Nobel Prize in 1997.

"Today nobody would argue that, at the very least, PrP plays some role in the diseased state," Telling says. "At one extreme, skeptics contend that it acts as a receptor for some yet-to-be-identified virus. At the other extreme is the protein-only hypothesis, in which the abnormal protein itself is the infectious agent and converts normal proteins into pathogenic ones.

"There are a lot of gray areas in between, which makes this at the same time extremely interesting and frustrating to work on," says Telling. "No virus has been found and no virus-specific nucleic acids have been identified, in spite of exhaustive efforts to detect them."

Photo of Michael Jernigan, Adrian Centers and Glenn TellingThird-year grad student Michael Jernigan, research associate Adrian Centers (pointing) and Glenn Telling (standing) discuss images of PrP, the prion protein, injected with a fluorescent agent that allows the scientists to study living infected cells.

Some very basic questions about prions remain.

What is their natural function? Telling says that prion proteins seem to play a role in maintaining appropriate copper levels in the brain, but beyond that, scientists don't have many good leads. (Copper helps supply blood to the brain, acts as a brain stimulant, and aids in nerve and brain function.)

Why are they so difficult to kill? Conventional means of sterilization (like cold, heat and ultraviolet radiation) that can successfully inactivate viruses have little or no effect on prions, which Telling says is yet another clue that this is an infectious agent unlike any other. Surgical instruments and lab equipment that may have come in contact with prions from brain tissue or lymph nodes are difficult to sterilize. As a result, European hospitals are using disposable surgical instruments as often as possible. It takes up to 1,080 degrees Fahrenheit to destroy prions. Deposited by disease-carrying animal carcasses, prions can lurk in soil for years, waiting to infect grazing animals that ingest them.

Why do these diseases take so long to incubate? Incubation periods ranging from months to decades frustrate scientists' efforts to nail down a point of infection. "The long incubation has something to do with the rate of conversion of normal proteins to pathogenic ones," says Telling. "If you are peripherally infected with these agents—say you ingest them—it takes time for them to infiltrate the central nervous system, and then it takes more time for replication and accumulation of prions to levels that cause permanent damage." Symptoms include impaired muscle control, loss of mental acuity, memory loss, depression, insomnia, and emaciation.

Prions don't cause Alzheimer's disease, but prion proteins share similar features with the non-infectious proteins that accumulate in Alzheimer's fatal plaque deposits. Future pharmacological interventions designed to prevent proteins from changing shape may be able to halt this domino effect and successfully treat prion diseases and other neurological disorders.

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