CMT Science Today

Are myelin and axons 'talking' to each other — and what are they saying?

Article Highlights:
  • Meet three MDA-supported researchers whose current work in Charcot-Marie-Tooth disease focuses on what happens at the molecular level of the disease.
  • Professors James Salzer, Thien Nguyen and Michael Granato are examining different ways in which myelin and axons interact with each other, and how that relates to nerve conduction and regeneration.
  • This article is part of a special Quest feature on CMT called In Focus: Charcot-Marie-Tooth Disease.
by Margaret Wahl on July 1, 2011 - 3:52pm

QUEST Vol. 18, No. 3

MDA-supported research in Charcot-Marie-Tooth disease is focused on figuring out what goes wrong at the molecular level in CMT-affected axons or the myelin sheaths that surround them, rather than on attempting to fix the problem directly or preserving nerve function in spite of it. A central theme emerging from the last decade of research is that myelin and axons require constant signals from each other to stay functional.

Here is a look at work being done by three leading MDA-supported CMT researchers.

The axon and the myelin sheath need each other, says James Salzer, an MDA-supported professor of cell biology and neurology at New York University.

James Salzer

Myelin’s essential role in allowing for speedy conduction of nerve impulses and providing protection and insulation around axons is well-known, he says.

In addition, recent studies suggest that myelin provides sustaining signals to axons that help keep them intact.

Loss of the myelin sheath — demyelination — is first a problem for nerve conduction and eventually a problem for the health of the axon itself. The latter isn’t well understood and is an area of intense study, Salzer says.

But what interests him the most right now is another aspect of peripheral nerve function — namely, how the axon and the myelin sheath signal the myelin-making Schwann cells to either keep making myelin or to stop making it.

In many forms of CMT, Salzer suspects, the “make myelin” signals are disrupted, either because of abnormalities in the axon or in the myelin sheath. His lab is focused on trying to restore myelin production.

“If you don’t have an axon, the myelin sheath will break down,” Salzer says. “The current view is that, as the axon breaks down, it releases signals that tell the Schwann cell to break down its myelin sheath.” The Schwann cell seems to go back to a more primitive, undifferentiated state.

A similar process may happen if the myelin sheath is abnormal, as it is in many forms of CMT, including the most common form, CMT1A. It seems myelin proteins that are overproduced or abnormal can cause the same kind of shutdown in Schwann cells as occurs when the axon is defective.

The vast majority of CMT1A cases are caused by overproduction of a myelin protein called PMP22, because of the presence of an extra PMP22 gene. Only a small percentage of CMT1A cases are caused by a mutation in the PMP22 gene that causes an abnormal PMP22 protein to be made.

Salzer’s group is working on reducing production of PMP22 by targeting a molecular pathway known as mTOR.

“It’s a key nexus in the control of a process called protein translation,” he says, referring to how proteins are produced from the genetic material known as RNA. “That’s a path that I’m sure is going to become a robust area in CMT research over the next couple of years.”

But it’s not the only thing on his to-do list. “Rather than targeting the extra protein itself,” he says, “one could instead go to the consequences of the extra protein or the misfolded protein and target the signals that it induces.”

Stopping dedifferentiation signals and keeping Schwann cells differentiated, so that they’re in their myelin-making state, is an avenue Salzer plans to explore.

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Michael Granato, a professor of cell and developmental biology at the University of Pennsylvania, has MDA support to study degeneration and regeneration after damage to peripheral nerves in an animal that’s getting a lot of attention in scientific laboratories everywhere: the zebrafish.

Zebrafish have more in common with mammals, including humans, than most people think, Granato notes. But unlike other animals, they’re transparent, which is a huge advantage. Scientists can see what’s happening in structures like peripheral nerves by looking at them under a microscope while the fish is alive and swimming.

Granato says his research team has begun to revisit — with state-of-the art tools — many old assumptions about peripheral nerves and the cells with which they interact.

“Seeing is believing,” Granato says. “This not only pertains to what’s happening in the nerve that’s damaged, but also to other cell types. What’s happening to those? How do they interact with the peripheral nerves? This is really the basis of understanding what’s going on.”

Two cell types that have been studied in connection with peripheral-nerve degeneration and regeneration are the myelin-making Schwann cells and the macrophages, cells made by the immune system. The word “macrophage” means “big eater,” and these cells gobble up debris from degenerating tissue in many different circumstances.

It’s long been assumed that macrophages go out to the damaged nerve some time after the damage has occurred, he says. But ongoing work in his lab studying nerve damage in the see-through zebrafish is focusing on the question of whether macrophages arrive even before the fibers start to break down.

Granato’s group is also using genetic tools to see how taking away macrophages would affect nerve regeneration in the zebrafish. If macrophage-supplied cleanup efforts had a positive effect on regeneration, attracting more macrophages to the site of an injury could be a therapeutic avenue. But if those efforts made matters worse, perhaps inhibiting macrophage recruitment would help.

Granato now has zebrafish with a mutation in the GARS gene, the cause of type 2D CMT. He’s testing the idea that nerve regeneration after injury is inhibited in these fish, and he believes figuring out the underlying molecular signals could ultimately be important for understanding and possibly treating some types of CMT.

Looking at something in real time in a model like the zebrafish “looks somewhat different” from what is seen in biopsy samples, he says. “We’re finding a lot of things that we hope will revise the literature regarding what people thought.”

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