After stimulation of NMDA receptors, prion-lacking mice suffer more damage to the hippocampus (top) than do mice with prions (bottom).

One function of prions, the Jekyll-and-Hyde proteins behind illnesses such as Creutzfeldt-Jakob disease (CJD) and mad cow disease, has been identified by Khosravani et al. The proteins calm brain cells, preventing them from dying of overexcitement.

Only when a prion folds incorrectly does it trigger brain-ravaging diseases like CJD. The normally shaped version, which all body cells carry, presumably performs an important task, but researchers haven't been able to pin it down. One hint comes from mice lacking the gene for prion protein. The animals are healthy, if somewhat forgetful. After a stroke or seizure, however, they suffer more severe brain damage than do control mice. Some of their brain neurons are also hypersensitive. These abnormalities implicate NMDA receptors, which respond to the neurotransmitter glutamate and to the drug NMDA. Overstimulation of NMDA receptors can allow lethal amounts of calcium into neurons.

Khosravani et al. tested whether normal prions dampen the activity of NMDA receptors. The researchers electrically stimulated slices of brain tissue from prion-making and prion-lacking mice. The same stimulation causes cells from rodents that don't harbor prions to respond more vigorously. The scientists saw similar results when they used NMDA to prod brain neurons. The drug provoked longer-lasting currents in the cells without prions. The cells paid a price for their excitability. Neurons from the prion-lacking rodents were more likely to die after a dose of NMDA than were cells from control mice.

The results from Khosravani et al. suggest that normal prions might exert their protective effect on neurons by switching off a particular subset of NMDA receptors that contain a subunit called NR2D. The work also suggests a mechanism for the brain damage caused by prion diseases. Malformed prions coax normal molecules to misfold. As the amount of normal protein falls, neurons lose their protectors and become more vulnerable to death by overstimulation.

Khosravani, H., et al.
J. Cell Biol.