Blocking a protein called CMTM6 in myelin-producing cells increases the thickness of nerve fibers and the speed at which electrical signals travel along their length, a mouse study has found.
Based on these findings, researchers argued that blocking the activity of this protein may be a valuable therapeutic approach to treat patients with Charcot-Marie-Tooth disease (CMT), in whom these nerve fibers tend to be thinner.
Findings were reported in the study, “CMTM6 expressed on the adaxonal Schwann cell surface restricts axonal diameters in peripheral nerves,” published in the journal Nature Communications.
CMT is caused by genetic defects that either damage nerve cells directly, or compromise the formation of the myelin sheath — the fatty substance that wraps around and protects nerve fibers (axons).
In addition to protecting nerve endings, the myelin sheath also allows electrical impulses to travel faster and more efficiently along axons between nerve cells. This has evolved as a mechanism in vertebrate animals to allow their axons to be thinner without compromising the speed at which electrical impulses traveled along their length.
Conversely, in animals that do not have a myelin sheath, such as invertebrates (those that have no backbone), axons must be thicker to ensure electrical signals continue to travel at high speeds.
However, the mechanisms limiting the diameter of myelinated axons in vertebrates, which also include humans, are unknown.
Researchers at the Max Planck Institute of Experimental Medicine and their colleagues investigated the possible link between Schwann cells and axon function and structure. Schwann cells are the myelin-producing cells that can be found along the surface of axons in the peripheral nervous system (network of nerves found outside the brain and spinal cord).
First, the team isolated proteins from Schwann cells in healthy mice that were part of the membrane surrounding the myelin sheath, adjacent to the axon surface.
A protein called CMTM6 (chemokine-like factor-like MARVEL-transmembrane domain-containing family member-6) was identified and selected for further analyses, as it was found in high levels and specifically localized in the contact point between Schwann cells and axons.
To explore its function further, investigators then created mice that were unable to produce the CMTM6 protein. In these animals, the diameters of axons were increased dramatically throughout the entire peripheral nervous system compared to normal mice. However, in all nerves and ages assessed, the ratio between myelin sheath thickness and axonal diameter remained normal.
“This indicates a role for CMTM6 in restricting the radial growth of axonal diameters,” the researchers wrote.
They also discovered electrical impulses traveled faster in mice that were unable to produce CMTM6. Moreover, compared to normal animals, these mice also reacted faster to heat simulation when placed on a hot plate.
“When we put the mice on a heated tile, the mice with thicker axons reacted significantly faster to the heat stimulus,” Maria Eichel, a doctoral candidate at the Max Planck Institute and first author of the study, in a press release.
However, CMTM6-deficient animals slipped more often than their counterparts when they were running over a grating.
“The animals were probably experiencing problems correctly coordinating the rapidly-transmitted stimuli,” Eichel said.
The team also confirmed that CMTM6 restricts the growth of axonal diameters after myelin formation, which is mostly completed in young adult mice. This restriction occurs in both myelinated and non-myelinated axons, without interfering with axon or myelin growth.
“In conclusion, CMTM6 emerges as a key player in the interactions between Schwann cells and axons. We speculate that counteracting the function of CMTM6 may restore the reduced axonal diameters and slowed [electrical impulse speed] in rodent models of Charcot-Marie-Tooth spectrum disorders,” investigators wrote.
“If confirmed in future preclinical assessment, this may allow developing a rational therapy concept toward functional improvement for neuropathy patients,” they concluded.
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