Prion Diseases: No Accomplice Needed

28 January 2010 (All day)

Fei Wang et al., Science

Spongy mess. Injected into mice, synthetic prions punch tiny holes in brain tissue (right), compared with healthy animals (left).

Since 1982, when neurologist and biochemist Stanley Prusiner first claimed to purify prion proteins, controversy has dogged the field. Do prions--misfolded versions of healthy protein linked to mad cow and other neurological diseases--infect and cause disease all on their own? Or do they need a partner in crime? Some say a new study provides the most compelling evidence to date for the "protein only" hypothesis. But die-hard skeptics remain unconvinced.

Five years ago, Prusiner reported the first major evidence that prions act alone. He and colleagues at the University of California, San Francisco, injected the brains of mice with prions they had created in the lab by misfolding normal prion protein, known as PrP. The mice came down with neurological disease. But the work had limitations: The rodents took more than a year to fall ill, and they had been bred to produce enormous amounts of PrP, raising questions about whether they were prone to prion disease anyway.

Jiyan Ma, a biochemist at Ohio State University in Columbus, along with colleagues there and in China, has solved these two problems by coaxing prions to misfold much like he believes they do naturally. Instead of misfolding the healthy prion protein, PrP, into amyloid fibrils, which have been linked to disease, the team combined the PrP with various blends of lipids--fatty molecules believed to misfold it in the cell. "This is like cooking," Ma says, getting the right combination of ingredients.

Eventually, Ma's group came up with a recipe that looked promising and injected it into the brains of 15 normal mice. Within about 130 days, all of the animals developed what looked like prion disease: their heads twitched, they lost muscle tissue, and they became lethargic. The animals died several months later. Control animals injected with a "harmless" solution stayed healthy, the team reports online today in Science.

To make sure it was prions that were making the mice sick, Ma performed a series of tests to prove infectious disease. Dissecting the animals' brains, he and his colleagues extracted tissue and injected it into the brains of healthy animals. Those animals then fell ill just like the previous group--and all showed evidence of prions.

This is something "that we and others have been trying to do for some time," says Claudio Soto, a neuroscientist at the University of Texas Medical School in Houston. "This is the evidence for the protein only hypothesis."

For those who were already convinced, the paper still "changes the rules of the game," says Adriano Aguzzi, a neuropathologist at the University of Zurich in Switzerland. That's because Ma and his colleagues managed to create large quantities of synthetic prion, which, Aguzzi believes, will make it possible to study prion structure in more detail than was previously possible.

But will it convince the skeptics? "On the face of it, it looks like they've turned tin into gold," says Laura Manuelidis, a neuropathologist at Yale University who has long doubted that prions cause disease all by themselves. (She believes that viruses are involved.) But Manuelidis worries that what Ma claims as a success--the speed with which the animals got sick--instead suggests that something went wrong. She wonders if the animals actually contracted scrapie, another prion disease, because of lab contamination. Ma wholeheartedly rejects this possibility: "There's no way" the mice could have contracted a natural prion disease like scrapie, he says, because his lab has not worked with naturally occurring prions.

  • Correction:

The story incorrectly states that Ma's lab has never worked with naturally occurring prions. In fact, it did, but not during the 2 years spent conducting the experiments described here.

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