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New study from Garcia lab shows a protein modification partially restores nerve insulation in mice

June 20, 2018

microscopic image of an isolated axon.

A microscopic image of an isolated axon from a mouse nerve, showing the segmented sheath that insulates it. The length of these segments, which is important for nerve function, is the focus of the new study. (Credit: E. Villalón)

The nerve fibers, or axons, of humans and other animals are surrounded by a protective sheath called myelin. This sheath, which functions to insulate the axons, does not form a continuous coating along the nerve fiber but is divided into segments or internodes. The length of these segments are important because they determine how fast or slow electric signals are propagated between the brain and the rest of the body.

When axons are damaged, this insulating layer can be repaired but the lengths of the segments are always too short, which can result in serious impairments. While scientists have long studied myelin and its role in disease, they have puzzled over why these internode lengths are always reduced when repaired.

Dr. Michael Garcia

Dr. Michael Garcia, Associate Professor of Biological Sciences

Now, in a study published in Experimental Neurology, the lab of Dr. Michael Garcia implicates a biochemical modification to a protein abundant in axons to the length of these segments.

The study adds to our basic knowledge of the mechanism that regulates myelination and remyelination and may provide a new target for translational studies aimed at improving treatment for demyelinating diseases, including multiple sclerosis, Charcot-Marie-Tooth, and Guillain–Barré syndrome.

For the study, Garcia and his colleagues, which included a team of graduate and undergraduate students, focused on an axonal protein called neurofilament-medium, or NF-M. NF-M has previously been shown to determine the diameter of axons. Researchers observed that this protein becomes phosphorylated (has a phosphate molecule attached to it) during the course of myelination when the internode length is optimal but that it maintains this phosphate throughout the entire process of remyelination when the internode length is short.

“When we saw that the internodes were too short when this protein is always phosphorylated, we asked what happens if you can’t phosphorylate this protein,” said Garcia, associate professor of biological sciences and corresponding author of the study

To find out, Garcia and his colleagues took advantage of a mouse model in which the region of the protein that is normally phosphorylated is deleted. They induced demyelination in the sciatic nerve of the mice and, following remyelination, removed the axons to measure the internode length. They found that the internodes were 30% longer as compared to wild type.

To further analyze the role of NF-M phosphorylation in regulating internode length, Garcia’s lab generated a second mouse model in which the same protein is modified in such a way that the axon responds as if NF-M is always phosphorylated even when it shouldn’t be during myelination, thus mimicking the conditions of remyelination. The researchers asked if having the protein phosphorylated all the time during myelination would result in shorter internode lengths, as occurs with remyelination. They removed the axons to measure the internode lengths and also performed behavioral tests to see if the mice displayed impairments to their sensory or motor abilities.

“In that animal, we found that mimicking constitutive phosphorylation reduced internode length by 16 percent during myelination as compared to wild type, which significantly slowed the speed at which axons relay information. We also found some behavioral deficits in the animal but only in the motor systems,” said Garcia.

Garcia said that, taken together, the findings show that the process of remyelination is cooperatively determined by communication between the axon and the Schwann cell, a finding contrary to previous research.

“It’s long been thought that Schwann cells, the cells from which the myelin sheaths are derived, determine the internode length cell autonomously. Our work shows that there is cooperative development with the axon to determine the length of the internode. We’re not sure what those communications are yet, but we know that part of it funnels through the phosphorylation status of this protein,” said Garcia.

Garcia said the NF-M protein may provide a possible target for translational studies aimed at improving nerve function following injury or disease.

“If we could prevent this protein from being ectopically phosphorylated, we could potentially make these internodes longer,” he said.

The potentially more exciting target, he added, may be the axon.

“We’ve looked at the axon as sort of a passive player in this process and that’s just not the case. The axon is providing some guidance. The question now is, if we were to change those guidance cues, could we increase the length of the internode following remyelination. That’s the next step down the road,” said Garcia.

Eric Villalon

Eric Villalón, Ph.D., is lead author of the new report.

Eric Villalón performed the research as a Ph.D. student in the Division of Biological Sciences and is first-author on the report. He said the findings will change how scientists approach the problem of restoring nerve function following injury or disease.

“Understanding what the major, seemingly unrelated, players in remyelination will change our approaches for generating a treatment to promote successful remyelination of axons to achieve normal functioning nerves,” said Villalón, who is now a postdoctoral fellow in the Christopher S. Bond Life Sciences Center. “We also demonstrate that successful recovery of nerve function following demyelination is not Schwann cell autonomous but depends on the axon, which also means that successful treatment will need to be approached from multiple angles.”

Teaming up with Garcia and Villalón on the study were a number of former MU graduate and undergraduate students, including Devin M. Barry, Ph.D. ‘12; Nathan Byers, BS ‘13; Maria Jones, Ph.D. ‘16; Jeffrey Dale, Ph.D. ‘14; and Natalie Downer, Ph.D., ’14. Dan S. Landayan, a former MU PREP Scholar, and Nigel A. Calcutt with the University of San Diego School of Medicine are also coauthors.

The report, titled “Internode length is reduced during myelination and remyelination by neurofilament medium phosphorylation in motor neurons,” is available online in the journal Experimental Neurology.

The research was supported by grants from the National Science Foundation, National Institutes of Health, University of Missouri Research Board, and the Missouri Spinal Cord Injuries Research Program.

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Written by: Melody Kroll

Related research strengths:
Cell Biology, Molecular Biology, Neurobiology
Related categories:
Graduate Studies