Mouse Study Offers Potential Evidence of New Therapeutic Target for CMT

Researchers discovered that the enzyme HDAC6 can serve as a potential therapeutic target in certain gene mutations related to Charcot-Marie Tooth (CMT) disease, according to new research with mice.

The study, “HDAC6 is a therapeutic target in mutant GARS-induced Charcot-Marie-Tooth disease,” appeared in the journal Brain.

CMT is a hereditary nerve disease that mostly affects the arms and legs, and is characterized by the progressive degeneration of motor axons in peripheral nerve cells, leading to muscle weakness and wasting, muscle cramps, and gait abnormalities.

The disease is classified as type 1 or 2, depending on whether degeneration affects the myelin sheath, which insulates the axons of brain neurons in type 1, or the axons itself in type 2. Patients can also have an intermediate phenotype with features of both.

Mutations in more than 80 different genes can cause CMT. This genetic and clinical variability hampers the discovery of common therapeutic targets.

Deficits in axonal transport — the cellular transport of RNA, proteins, lipids, and organelles — can cause neurodegeneration and peripheral neuropathies. The transport of axons depends on microtubules, which provide the “tracks” for transportation.

Within the microtubules, a chemical process known as acetylation of the protein alpha-tubulin takes place, which is also crucial to axonal transport. HDAC6, a key enzyme in the acetylation process, is a relevant clinical target in Alzheimer’s and ALS, and has also been related to Charcot-Marie-Tooth. 

Mutations in enzymes known as aaRS, which are involved in protein production, have been shown in CMT disease and related peripheral neuropathies. In particular, a mutation in a gene known as Gars, which belongs to the aaRS family and provides instruction to make the protein GlyRS, causes degeneration of motor and sensory nerves in mice.

Work with flies further clarified the link between mutations in aaRS genes and peripheral neuropathies. However, studies in yeast, flies, and mice showed that only some of the mutations found in patients with CMT type 2 alter acetylation. So the effect of alterations in aaRS enzymes does not seem to be solely due to this chemical process.

Researchers evaluated the therapeutic utility of inhibiting HDAC6 in CMT disease. They also analyzed whether different genetic forms of CMT present similar hallmarks, which would indicate a common disease mechanism.

In molecular biology experiments, the team found that GlyRS and HDAC6 interact, and that decreasing the level of one of these proteins causes a parallel reduction in the amount of the other.

In addition, using a mouse model of CMT2, which has a Gars mutation and exhibits motor and sensory axonal degeneration (including reduced muscle mass) from a young age, researchers observed decreased acetylation of alpha-tubulin in peripheral nerve tissue and altered axonal transport of mitochondria (which provide power to cells throughout the body).

Inhibiting HDAC6 with a compound called tubastatin A was found to improve acetylation and axonal transport, which led to improved motor and sensory behavior, as well as restored muscle innervation by axons.

“In conclusion, with this study we further confirm the involvement of HDAC6 in degenerative disorders such as CMT and we hypothesize that HDAC6 could be an important therapeutic target for peripheral neuropathies in general,” the researchers wrote.