Survivors. Despite prion deposits (arrows, insert), mouse brains sealed spongy holes.

Mice Saved From Madness

Prion diseases are thought to herald certain death, because no therapy can slow or stop the progression of "mad cow disease" or other ailments linked to these misfolded proteins. But now, researchers have managed to reverse disease in afflicted mice, even while some prions remain in their brains. The work challenges the conventional view of how the disease hurts the brain and lends hope that treatments might one day be possible.

One puzzling aspect of prions is that attempts to halt the prions haven't improved symptoms, leading some researchers to wonder exactly what is harming the brain. John Collinge, head of the Prion Unit at the Medical Research Council in London, and Giovanna Mallucci, along with their colleagues, decided to target not the prions but the healthy protein from which mammalian prions originate. This protein, PrP, is present throughout the body. In mice and other animals, it morphs into a prion form called PrP-scrapie, which then warps other PrP proteins.

The researchers created mice that were normal at birth, but at 12 weeks began churning out an enzyme that eliminated the fodder for prions--the PrP protein--from neurons alone. A few weeks after the mice were born, Collinge's group injected them with prions. By 12 weeks, their brains were full of spongy holes. Nevertheless, prions hadn't yet infiltrated the animals' neurons, and the mice weren't showing symptoms. Regular mice infected with prions soon succumbed to prion disease.

The experimental mice, however, did remarkably well. At 12 weeks, the PrP gene in their neurons had shut down. Within days, the neurons ran out of normal PrP protein. Without it, prions did not infect the neurons. More than a year later, these nine mice still "live a normal life," says Collinge, and the holes in their brains have inexplicably healed. Also surprising, the group reports in the 31 October issue of Science, was that non-neuronal brain cells still contained wads of prions, but the mice didn't seem bothered.

The work adds to the growing body of evidence that the prion form of PrP--at least, when in non-neuronal brain cells--might not be the poison it's viewed as, says Adriano Aguzzi, a neuropathologist at the University of Zürich in Switzerland. Aguzzi thinks the toxin could be a still-unidentified form of PrP that may fleetingly appear when normal PrP is morphing into the scrapie form. Whether or not this is the case, the Collinge and Mallucci study offers a glimmer of hope. "In the past, neurodegenerative diseases were a death sentence," says Ai Yamamoto, a neurobiologist at Memorial Sloan-Kettering Cancer Center in New York City. Now "there's a possibility, at least in mice, that you can recover."

Related sites
Medical Research Council Prion Disease Unit
Mad cow disease home page