Normal and not. In a healthy mouse peripheral nerves are healthy (left), but in one without the prion protein they suffer a loss of myelin (right).

Adriano Aguzzi, et al., Nature Neuroscience

Prion Protein Keeps Nerves Happy

Misshapen proteins called prions are thought to wreak havoc when they're let loose in the brain, as happens in mad cow disease. But despite their bad rap, prions start life off as a normal, healthy protein, called PrP. PrP is everywhere in the brain--but what it does has long been mysterious.

There's hope that by disentangling PrP's normal job, prion diseases will become easier to understand. A team of scientists now says that PrP plays a key role in maintaining myelin, a fatty substance that forms a sheath around nerves and helps transmit nerve signals. They also found that mice without PrP in certain nerve cells suffer from a demyelinating disease that closely resembles one seen in people.

"If you want to understand pathological function, maybe you have to understand normal function," says Adriano Aguzzi, a neuropathologist and longtime prion researcher at the University of Zurich in Switzerland, who led the work. Eleven years ago, a Japanese group published a paper suggesting that mice without PrP had damage to their peripheral nerves, a finding that intrigued Aguzzi. With his postdoctoral fellow Juliane Bremer and their colleagues, he set out to probe this further. First, the team examined five strains of mice lacking the PrP gene and found that they all showed this peripheral nerve damage by 10 weeks of age. But that didn't answer the question of what, exactly, was behind this nerve damage.

To learn more, the group looked at 1-year-old mice and found that their sciatic nerve, the large nerve in the back that runs into the legs, had lost myelin. Then, they studied mice that lacked PrP in some cells but not in others to see which cells were behind the demyelination. The result was a surprise: When PrP was present only in axons, the fibers that conduct electrical impulses, it prevented disease. But when it was lacking in axons but present in the so-called Schwann cells that actually form the myelin sheath, the mice got sick. Even though the Schwann cells are the ones affected when PrP is missing, the protein must be present in axons to prevent disease, the researchers report online this week in Nature Neuroscience. Aguzzi theorizes that PrP is a signaling molecule in axons that's needed to "keep Schwann cells happy."

This gets at "one of the important things we still do not know--we still do not know what is the normal function of the prion protein," says Claudio Soto, a neuroscientist at the University of Texas Medical School in Houston. There had been suspicions, he says, that axons were somehow involved, but this work takes that one step further, tying PrP to myelin.

Aguzzi is now interested in learning more about whether PrP might have a hand in human demyelinating diseases, particularly a rare type of hereditary neuropathy, and recently received funding to study this. Another, more common disease that leads to loss of myelin, multiple sclerosis, seems unconnected to PrP's actions because myelin is lost in the central nervous system, not peripherally as it was in the current study. But other human diseases "look very similar to what we see in these mice," notes Aguzzi, who's eager to find out whether prion proteins are involved.