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A simple recipe for cerebral disaster

By Laura Stephenson Carter

What do you get when you mix a pinch each of normal prions and polyanions with a dash of copurified lipid molecules? A brew of infectious prions.

A DMS team led by biochemist Surachai Supattapone, M.D., Ph.D., has published the first report of spontaneous generation of infectious prions in a test tube. The paper was in the June Proceedings of the National Academy of Sciences.

Prions are normal proteins found in the brain that become infectious when they misfold. As they slowly convert from the normal to the infectious form, they can cause rare, deadly brain disorders called transmissible spongiform encephalopathies, such as mad cow disease in cows, scrapie in sheep, and Creutzfeldt-Jakob disease (CJD) in humans.

Rare: The Dartmouth work provides a biochemical model of the naturally occurring, but very rare, sporadic CJD, says Supattapone. And, adds his lab manager Nathan Deleault, the first author on the study, "it gives us a glimpse as to how this process occurs in the brain."

The findings, Supattapone notes, also provide the best support to date for the protein-only hypothesis—that unlike other pathogens, which rely on nucleic acid containing DNA or RNA to replicate, a prion can propagate without nucleic acid. Some scientists are critical of this idea and think prion diseases are caused by an asyet- unidentified slow virus. But others—like Supattapone, who trained in the lab of Nobel Laureate Stanley Prusiner,M.D., a prion pioneer at the University of California, San Francisco (UCSF)—prefer the protein-only hypothesis.

The study was also important in that it was "the first time that an infectious agent has been created from noninfectious components," says Supattapone. It was "very surprising." Surprising enough that he wanted to be sure the samples hadn't been contaminated with infectious prions from other research. So his team ran the experiments again in a colleague's prion-free lab—and reproduced the results.

At DMS since 2001, Supattapone has been slowly unraveling the mysteries of prion disease. Next, his team hopes to determine how the interaction between polyanions—molecules with repeated, negatively charged ions that are found naturally in the brain—may contribute to spontaneous infectious prion formation.

Patent: Prion researchers are seeking ways to prevent, diagnose, and treat prion disease. And they're trying to "develop ways to break the transmission cycle," says Supattapone. He and Prusiner recently received a patent for an antiseptic compound they developed at UCSF. Called Priox, it can inactivate infectious prions on surgical blades and other surfaces.

Still, Supattapone is modest about his achievements. So far, he says "all we've done is create a biochemical model, which mimics what occurs naturally in the brain." But he doesn't plan to stop there.

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