New insight into cause of Charcot-Marie-Tooth disease

Image Credit: Toward a Cure for Charcot-Marie-Tooth Disease, Scripps Research

The nervous system is the body’s control center, which is extremely fast in decoding messages from the different nerves in the body. This network should be intact and healthy. When something is wrong with the network, it affects the brain’s main functions.

Neurological diseases attack the main parts of the nervous system, namely the brain, spinal cord, and the nerves. The neurons or nerves send messages to and from the brain, to sustain life and the body’s basic activities. Conditions that affect any part of the nervous system can cause chaos within the body.

One of the rarest forms of neurological impairment, the Charcot-Marie-Tooth (CMT) disease affects about 1 in 2,500 people in the United States. The disease, which was named after the three physicians who first identified it in 1886, is characterized by a group of disorders that affect the peripheral nerves.

Since the condition is very rare, there had been little information on its root cause. But, previous studies have shown that mutations on more than 90 genes have been associated with the disorder. The thing is, a person only needs one gene mutation for the disease to emerge. Despite having many genetic mutations tied to the illness, CMT negatively impacts the patients’ peripheral nervous system.

The peripheral nervous system (PNS) is the part of the nervous system that contains all the nerves that are located outside of the central nervous system (CNS) or the brain and spinal cord. The major role of the PNS is to connect the central nervous system to the skin, limbs, and organs. They are the ones who detect a stimulus and in turn, send messages to the brain or the body’s control center.

Genetic mutations of CMT

In a new study, published in the journal Proceedings of the National Academy of Sciences (PNAS), the researchers focused on ubiquitous enzymes, called aminoacyl-tRNA synthetases, which are the largest protein family tied to the CMT disease.

"The genetic mutations of CMT are well understood, but the disease-causing mechanisms are still a mystery on a molecular and cellular level. In our latest study, we took a bottom-up approach, looking for commonalities among different mutations in one of these genes in the hope that we will uncover new insights for treatment,” Scripps Research Professor Xiang-Lei Yang, PhD, lead researcher, said in a statement.

Aminoacyl-tRNA synthetases work by attaching themselves to appropriate amino acids to trigger the initial step in creating new proteins. Proteins, which are the building blocks of life, including hormones, blood, bones, and skin, are vital for survival.

Loss of function disappeared

The researchers know that previous studies have examined that the mutated enzymes and found that the disease-affected aminoacyl-tRNA synthetases weren’t working well compared to their healthy counterparts, termed as “loss of function”.

However, when the researchers used samples from patients, they explored and viewed the enzymes in their cellular environment. They found that any loss of function had vanished when the mutated enzymes were combined with other healthy enzymes existing in the cell.

The researchers further focused on the mutated enzyme’s shape instead of the function. They used biophysical and biochemical analysis techniques, and they found that the mutated enzymes had unusual extended shapes, allowing for extra surface area. With an extended shape, they could provide unwanted contact with nearby proteins, leading to an unhealthy state.

Future research endeavors

The researchers wanted to explore more into the link between the many forms of CMT, which can help formulate new therapies and possible treatments for CMT.

"One in 2,500 people have CMT, and today there is no therapy available to help them. We believe the best path to treatment is to start by understanding what is fundamentally wrong in the biological environment of this complex neurodegenerative disease,” Yang explained.

What is Charcot-Marie-Tooth disease (CMT)?

The Charcot-Marie-Tooth (CMT) disease is an inherited neurological disease that causes progressive and slow degeneration of the muscles in the lower legs, foot, hand, and forearms. It also leads to mild loss of sensation in the toes, fingers, and the limbs.

The condition is inherited, which means it can be passed from one generation to another, and it runs in families. The first sign of CMT is a high-arched foot or gait disturbances. The other symptoms of the condition include problems in balance and hand function, leg cramping, partial sight or hearing loss, normal reflexes, and in some people, scoliosis or the abnormal curvature of the spine.

There are two types of CMT, type 1 and type 2. CMT type one affects the peripheral nerves’ axons, which is the part of the neuron that transmits signals to the muscles. In the axon, the myelin sheaths diminish, altering the axon’s function. In CMT type 2, which is less common, the axon’s responses are decreased due to a defect in the axon itself.

Journal reference:

Blocquel, D., Sun, L., Matuszek, Z., Li, Sheng, Weber, T., Kuhle, B., Kooi, G., Wei, N., Baets, J., Schimmel, P., Yang, X.L. (2019). CMT disease severity correlates with mutation-induced open conformation of histidyl-tRNA synthetase, not aminoacylation loss, in patient cells. Proceedings of the National Academy of Sciences. https://www.pnas.org/content/116/39/19440