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New therapeutic targets identified in Charcot-Marie-Tooth disease

Research conducted at the Institute of Neurology of University College London (UCL) and just published in the Proceedings of the National Academy of Sciences USA has identified a set of novel therapeutic targets for a subtype of Charcot-Marie-Tooth disease (CMT), a human condition that currently has no effective treatments. Surprisingly, the scientists also uncovered a previously unappreciated developmental element to this peripheral neuropathy, which has important implications for the timing of treatments.

CMT is a genetic disorder causing the deterioration of peripheral nerve cells called motor and sensory neurons. Motor neurons connect the brain and spinal cord to muscles allowing voluntary muscle contraction, while sensory neurons come in many different types that allow them to convert specific external stimuli, such as touch and pain, into signals within the neuron that are transmitted back to the brain. When these nerve cells start to malfunction in CMT, patients suffer from muscle weakness and impaired sensation.

The 2D subtype of CMT (CMT2D) is caused by mutations in a gene called GARS, which produces a protein found in all cells of the body. The reason why mutations selectively affect the nervous system of CMT2D patients was a mystery.

Using mouse models of the disease, the group of scientists lead by James N. Sleigh and Giampietro Schiavo showed that mutations in GARS caused the sensory nerves of CMT2D mice to mistakenly switch their identity before birth.

This result was surprising because CMT is classically thought to be a neurodegenerative disease, where the peripheral nerves normally decline during adolescence or adult life. This finding in mice indicates that CMT2D, and perhaps CMT more generally, may arise from a complex relationship between developmental defects and degeneration of the nervous system. If this is shown to be the case in CMT patients, this discovery has profound consequences for the timing of treatments for this disease – patients should be treated during childhood/adolescence, before appearance of clinical symptoms.

Searching for an explanation for this alteration in sensory identity, these UCL scientists discovered that the mutant GARS protein incorrectly interacts with a set of nervous system-specific factors, known as the Trk receptors, which are vital to the development and differentiation of sensory nerves.

This aberrant association of mutant GARS with the Trk receptors, not only provides a possible explanation for the selective nervous system nature of CMT2D pathology – only cells that express specific arrays of Trk receptors are susceptible to mutant GARS pathological effects – but could also provide useful targets for therapeutic intervention.

 

Abstract from the publication:

http://www.pnas.org/content/early/2017/03/27/1614557114.abstract

James N. Sleigh Page

http://www.ucl.ac.uk/ion/departments/sobell/Research/Post-Doc-Fellows/JamesSleigh

Schiavo Laboratory Website:

https://www.ucl.ac.uk/ion/departments/sobell/Research/GSchiavo

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