Sensory neuron fate is altered in human neuropathy caused by Gars mutations

What is it about?

Charcot-Marie-Tooth disease (CMT) is a genetic condition affecting the peripheral nerves, which connect the brain and spinal cord to the rest of the body. This includes the motor neurons, which carry messages to our muscles, telling them to contract, and the sensory neurons, which convert specific external stimuli, such as touch and pain, into signals that are transmitted back to the brain. CMT causes the motor and sensory neurons to become damaged and eventually die. This leads to muscle weakness and numbness in some parts of the body. The 2D subtype of CMT (CMT2D) is caused by mutations in the GARS gene, which leads to the production of a faulty GARS protein. Although the GARS protein is found in all cells of the body, only the nervous system is affected by CMT2D. In this study, we monitored the sensory nervous system of CMT2D model mice, and found that the sensory neurons did not develop properly. This developmental problem was unexpected as CMT is considered to be a neurodegenerative condition, where the peripheral nerves deteriorate during adolescence or adult life. Potentially explaining this defect, we found that the mutant GARS protein binds to and disrupts the activity of a set of proteins called Trk receptors, which are vital to the development of sensory nerves.

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Why is it important?

Although this study was carried out in cells and mouse models, its findings give us a better understanding of what is going wrong in the peripheral nerves of people with CMT2D. It suggests that CMT2D, and perhaps CMT more generally, may be caused by a combination of developmental problems and degeneration of the nervous system. If this is shown to be the case in CMT patients, this discovery may have important implications for the timing of treatments. It suggests that patients should be treated before the appearance of clinical symptoms e.g. during childhood or adolescence. The knowledge gained from this study could also be helpful for the development of future treatments. It highlights the role of Trk receptors in CMT2D, which could potentially be therapeutically targeted.