October 31, 2003

Gene tweak halts mad cow disease

Toxic by-product, not rogue proteins, may cause fatal brain wasting.

by Tom Clarke
Nature News

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Clumps of rogue proteins are not the cause of fatal conditions such as mad cow disease, but merely a symptom, hints new research. The insight could ultimately help to treat the degenerative brain diseases - the hunt is now on for the real culprit.

BSE in cows, scrapie in sheep, chronic wasting disease in deer and variant Creutzfeldt-Jakob Disease in humans occur when an animal or person is infected with a misshapen form of proteins called prions. The molecules accumulate in the brain as they twist healthy prions into their own image.

Mutant prions accumulate in dying brain cells and spongy gaps open up in the brain, causing loss of coordination, confusion, mental decline and eventually death.

Giovanna Mallucci and colleagues at the Institute of Neurology in London halted the conversion of healthy prions to rogue ones in genetically modified mice1.

The mice recovered and lived as long as uninfected animals, despite the continued presence of tangles of abnormal prions in their brains.

"It's the conversion process, not the accumulation of protein, that is key to the disease," concludes Mallucci. Team leader John Collinge suspects that the switch may produce a toxic by-product, an intermediate form, or may deplete a factor that is crucial to brain-cell survival.

"This is a milestone in prion research," says Adriano Aguzzi of University Hospital Zurich in Switzerland, who previously hinted that accumulating prions do not kill nerve cells. It is "wonderful" for showing that shutting off conversion actually allows brains to recover, he says.

Aguzzi's and Collinge's teams are now looking for the fatal factor. A first step is test-tube screening for toxic properties among proteins that twist healthy prions. "This work is part of a long-term strategy to develop therapies for these diseases," Collinge says.

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