The brains of prion disease victims are full of empty spaces where healthy neurons once thrived. They are also clogged with clumps of prion protein (PrP) in a misfolded form called PrP Sc .

PrP Sc is thought to be the infectious agent, but not the cell killer. "Now our work provides a mechanism for how PrP, a normal protein present in everybody, becomes extremely toxic to humans," says researcher Yiyan Ma, now at Ohio State University.

All mammals, including humans, make PrP. A newly manufactured prion travels to the cell's membrane, to be expressed on the surface. Occasionally, these prions are misfolded during manufacture. If this happens, a natural set of "garbage disposal" enzymes called proteasomes move in to destroy the mutants.

But Ma and his colleagues found that infection with PrP Sc s seems to somehow overwhelm this quality control machinery. Once this has happened, different misfolded prions can accumulate in the cell and kill it, even at very low levels.

Treatment hopes

"We do not know exactly how these misfolded PrPs kill cells, which is obviously the key. We are now working on this," Ma told New Scientist . But the findings suggest that if proteasome stimulating drugs could be developed, they might form an effective treatment.

The team worked on individual cells and on genetically modified mice. Introducing proteasome inhibitors led to a toxic build-up of misfolded prions in cells. And mice genetically engineered to accumulate misfolded prions in their cells developed neurodegeneration and a loss of muscle control similar to that found in patients with vCJD.

The research does not reveal how the presence of PrP Sc s overwhelms proteasome activity. "But PrP Sc might change a signalling pathway within the cell," suggests Ma.

Spontaneous formation

In a separate paper, Ma and Susan Lindquist at the Whitehead Institute for Biomedical Research also showed that accumulated misfolded PrP can convert to PrP Sc . And they demonstrated that when PrP Sc comes into contact with other prions, they become converted to its mutant form, propagating the infection.

The team also showed that PrP Sc can sometimes spontaneously form in cells, possibly explaining the development of sporadic prion diseases, such as CJD.

Proteasome inhibitors are currently in trials as treatments for some diseases, such as cancer. The new work suggests they should be used with caution in people who may have been exposed to infectious PrP Sc prions, such as people who might have eaten infected beef at the height of the BSE epidemic in the UK in the late 1990s, the researchers say.

So far, 117 people in the UK have died from definite or probable vCJD. Predictions of the ultimate extent of the epidemic range from several hundred people to many thousands.

"We are now working on ways to stop the misfolded PrP accumulation that kills cells," says Ma. But prion diseases usually have long incubation times. To be truly effective any treatment would have to start before the onset of symptoms, by which time large numbers of brain cells would already have been destroyed.

Journal reference: Science (DOI: 10.1126/science.1073619, DOI:10.1126/science.1073725)

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