New study unveils developmental aspect to CMT

Published Date
Dr James Sleigh & Dr Jenny Sharpe

Researchers at the University College London (UCL) Institute of Neurology have discovered developmental problems in a mouse model of Charcot Marie Tooth disease (CMT) type 2D. This could have important implications for the timing of treatments in patients.

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 from the brain and spinal cord 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.

CMT 2D 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 CMT 2D.

What did the researchers do?

Dr James Sleigh and Dr Giampietro Schiavo from UCL studied mouse models of CMT 2D and monitored the development of their nervous systems. They found that the sensory neurons in the mice 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.

In order to better understand the cause of the developmental problem, the researchers investigated the effect of the faulty GARS protein in nerve cells grown in the laboratory. They found that it disrupts the activity of a set of proteins called Trk receptors, which are vital to the development of sensory nerves. This may explain why CMT 2D specifically affects the nervous system.

A section of a mouse dorsal root ganglion (DRG), which is a collections of nerve cells essential for sensing the external environment. These structures are often studied in mouse models of peripheral nerve conditions, as their composition is similar to that of humans. This section has been stained to highlight different types of sensory neuron. For example, the green nerves are involved in something called proprioception (sensing the internal body position in space), whereas the red nerves are important for sensing touch.

What does this mean for people with CMT?

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 CMT 2D. 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 CMT 2D, which could potentially be therapeutically targeted.

This study was published in scientific journal, Proceedings of the National Academy of Sciences (PNAS).

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