Prions' Deadly New Twist

Prions, common proteins that when misfolded are thought to cause "mad cow disease" and its human equivalent, may have another deadly form. In today's issue of Science, researchers show that the same protein that causes cows to keel over can, with a small mutation, kill mice in weeks by inserting itself into the membranes of their brain cells. The intruder prion may also be behind a fatal neurodegenerative disease in people.

The prion protein (PrP) is thought to turn deadly when it folds improperly into a form called PrPSc. Scientists believe that in this mangled form, the prion piles up in the brain and induces other proteins to misfold, thereby killing the cells and the patient. But this can't be the whole picture, because in a few brain diseases linked to mutations in PrP, patients don't seem to have the deadly clumps of PrPSc.

A team led by Stanley Prusiner at the University of California, San Francisco, stumbled on a clue to how these mutated prions might kill while studying prions from healthy hamsters. They noticed that occasionally the prions were not simply hooked onto the surface of a cell, but were poking through the cell membrane. They found that certain mutations in a 30 amino acid stretch of the prion would force most or all of the prion protein into the cross-membrane form, called PrPctm. The researchers were surprised to find that two of the mutations, when introduced into mice, led to a degenerative brain disease that proved fatal within 2 months.

The researchers suspected that Gerstmann-Straussler-Scheinker disease (GSS), an inherited neurodegenerative disease that strikes at about age 50 and kills within 2 to 5 years, might likewise result from prions in PrPctm form, especially because these patients are known to have a mutation in the same region as the mice. The researchers checked the brains of a couple of patients who had died from GSS and found that while they had none of the traditionally toxic PrPSc, a portion of their prions were in the PrPctm form, suggesting that the same mechanism is at work in both mice and man.

"It's an interesting correlation" between GSS and mutations for membrane-bound prions, says Suzette Priola, a prion researcher at the National Institute of Allergy and Infectious Diseases' Rocky Mountain Lab in Montana. "But a direct link needs to be proven," especially because the mouse and human mutations are not identical. The study also seems to contradict others that have found the misfolded prion PrPSc in GSS patients.