Researchers have identified a pathway common to several types of axonal peripheral neuropathies (APNs), including multiple forms of Charcot-Marie-Tooth (CMT) disease, and have identified a possible drug target that could help treat the disorder. The study, which was published in Science, was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.
APNs cause the body's peripheral nerves to wither and degenerate, which makes them unable to send messages to the muscles or to transmit sensory signals back to the spinal cord. While usually not life-threatening, APNs typically result in some measure of disability.
Genetic studies have shown that many APNs are caused by mutations that affect how proteins are built within cells. Proteins are made by first transcribing the DNA code into messenger RNA (mRNA). The mRNA is then transcribed by transfer RNA (tRNA) molecules that string together amino acids in the proper sequence like building a train track. The mutations underlying APNs affect the enzymes responsible for adding amino acid blocks to tRNA.
Previous work in flies showed that these mutations inhibit cells' ability to make proteins. This causes stress within the motor neurons affected by APNs, particularly through a mechanism called the integrated stress response (ISR), ultimately leading to degeneration of nerve structures. Of the proteins previously implicated in the activation of the ISR, one of them, GCN2, had also been connected to defects in protein translation.
Using a mouse model, the researchers looked at APN mice that were also missing GCN2. These mice began to develop symptoms of the disease around two weeks of age, but the disease did not progress much beyond the initial stages. When the APN mice were instead treated with a drug to stop GCN2 from working, they showed improvements in many symptoms. Interestingly, while improvements were seen in both male and female mice, a greater effect was seen in males.
The study was supported by NS054154, NS113586, NS100328, NS065712-08, and OD020351.
