Prion protein is not all bad

A molecular Dr. Jekyll finally has a day job—as an electrical lineman. A new study suggests that the normal form of prion protein helps maintain the insulation that speeds electrical signals along nerve fibers.

In its twisted Mr. Hyde form, the prion protein causes fatal brain-wasting diseases, such as mad cow disease in cattle and Creutzfeldt-Jakob disease in people (SN: 8/16/08, p.20). But the normal form of the protein, which is typically found in neurons in people and other mammals, is also a good guy, a new study shows. The protein may direct cells called Schwann cells to wrap around neurons and produce myelin, a type of insulation that aids electrical communication between nerve cells. This newly discovered role for the normal form of the prion protein — designated PrP(C) or just PrP — could link the protein to nerve disorders called peripheral neuropathies, researchers led by Adriano Aguzzi, a neuropathologist at the University of Zurich, report in the Jan. 24 Nature Neuroscience.

Much attention has focused on how the infectious form of the protein leads to disease, but it has been a mystery what the prion protein’s normal function might be. Some other functions for the protein have been proposed (SN Online: 7/14/08) but haven’t been confirmed.

“This question of the normal function of PrP has become an obsession for me,” says Aguzzi.

In the new study, Aguzzi and his colleagues studied several different strains of genetically engineered mice that lack the prion protein. The researchers found that mice from all of the strains had abnormal myelin sheaths around their sciatic nerves, long nerve cells that run from the lower back to the foot. Electrical signals traveled more slowly down the sciatic nerve fibers in mice that lacked prion proteins compared with mice that had intact prion proteins, the team found. Restoring prion proteins to the nerve cells allowed the myelin sheath to be repaired. But putting prions back into Schwann cells did not. That result suggests that the prion protein is needed in the neuron but not in the Schwann cell.

Further experiments showed that the repairs happened only when the prion protein could be snipped in half. This cleavage frees part of the protein, which then signals Schwann cells to make myelin. The researchers don’t yet know what cuts the prion protein or how Schwann cells detect the signal.

A wide variety of functions have been proposed for the prion protein, but researchers have not been able to replicate results using different strains of mice. The new study finds the same results for many genetically different types of mice.

Surachai Supattapone, a biochemist and neuroscientist at Dartmouth Medical School in Hanover, N.H., says Aguzzi’s team really has discovered prion proteins’ day job. “Everything has been done that makes me comfortable that PrP communicates with Schwann cells to promote myelination,” he says.

Schwann cells make myelin only for peripheral nerve cells, neurons that connect the organs and limbs to the brain or spinal cord, which make up the central nervous system. It’s not clear what the prion protein does in the central nervous system.

If the prion protein does play a role in myelin formation, that could pose a problem for gene therapy that would remove PrP from cattle and other animals as a strategy to prevent prion diseases, says Claudio Soto, a neuroscientist at the University of Texas Health Science Center at Houston. He and colleagues have genetically engineered cattle that lack the prion protein. Mice and other animals that don’t have PrP can’t be infected with prion diseases. But the question remains whether lacking PrP can cause peripheral nerve problems, Soto says.

“It really has to be taken into consideration as a normal biological function for the prion protein,” Soto says. “This is an interesting paper that needs to be corroborated.”