Critical for Coating: Protein directs nerve-sheath construction

Just as plastic coatings insulate electrical wires, myelin sheaths surround nerve fibers in the body. In addition to protecting the fibers, these fatty sheaths speed up the message-carrying impulses and keep extraneous signals from interfering with impulses traveling along the fibers. Although scientists have known about myelin for several centuries, mystery has shrouded the delicate interplay between nerve cells and the glial cells that produce it.

In the Sept. 1 Neuron, scientists demonstrate that the protein neuregulin-1 type III (NRG1-III), which is produced by nerve cells, is essential to triggering glial cells to make myelin. This advance could lead researchers to develop more-effective treatments for several neurological diseases, including multiple sclerosis (MS), which is caused by a misguided immune system assault on myelin, says study coauthor James L. Salzer, a neuroscientist at New York University School of Medicine.

The emerging picture of myelin production points toward a new medical strategy that combines the suppression of inflammation in MS patients and the rebuilding of myelin sheaths, or remyelination, to reverse nerve damage, says Salzer.

“We know that if we had consistent remyelination, we wouldn’t have MS,” says Klaus-Armin Nave, a neurogeneticist at the Max Planck Institute of Experimental Medicine in Göttingen, Germany.

Scientists have known for a decade that nerve cells make neuregulins that induce the growth of nearby glial cells. Further work associated NRG1-III, in particular, with nerve cells surrounded by a thick, robust myelin coating.

To determine whether NRG1-III is necessary for myelin production, Salzer and his colleagues grew two cell types together in lab dishes. The mix of unmyelinated nerve cells from embryonic mice, cells that don’t produce NRG1-III, and glial cells from adult rats showed no myelination. However, when the researchers genetically engineered the nerve cells to make and release NRG1-III, the glial cells promptly enveloped them with a thick myelin coating.

Not all nerve cells in the body are myelinated. Salzer’s group found that the less NRG-1 a nascent nerve cell cranks out, the thinner the myelin sheath provided by glial cells.

In this way, nerve cells are determining their own fates, says Brian J. Popko, a molecular biologist at the University of Chicago.

It’s not clear why some nerve cells set themselves up to be superhighways of the nervous system, while others are content to be back roads. In any case, Salzer says, NRG1-III is instrumental in creating the difference.

“This paper shows that one molecule is regulating that distinction,” Popko says. “This is clearly an extremely important discovery.”

The work so far has concentrated on peripheral nerves—those outside the brain and spinal cord. These nerves control movement, sensation, and other bodily processes. Some diseases, such as Guillain-Barré syndrome and chronic inflammatory demyelinating syndrome, stem from myelin loss in this periphery. “This work is highly relevant to those disorders,” Popko says.

In contrast, MS is a disease of the central nervous system. “We assume that the language with which glial cells talk to nerve cells in the central nervous system is to some extent the same” as that in the periphery, says Nave.

If that’s the case, Salzer says, the NRG1-III findings “could provide a clear avenue for new strategies in fighting MS and other myelin disorders.”

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