About 1 in 2,500 people have a degenerative nerve disease called Charcot-Marie-Tooth (CMT). The disease is typically diagnosed in children, who may lose their ability to walk and use their hands for fine motor skills. There is still no cure. Scientists from the Scripps Research Institute (TSRI) have now shown a pathway for the development of treatments for the CMT2D disease subtype. As reported in the journal Nature Communications, it may be possible to reverse the disease using a small molecule to restore normal protein function in the nervous system. It is important to underline that the study reveals how a better understanding of the fundamental causes of CMT can point researchers towards a cure for other subtypes. Here is a puzzle: CMT2D is caused by mutations in an enzyme called GlyRS (glycyl-tRNA-synthase), which is expressed by cells throughout the body. This enzyme inserts amino acid glycine into growing proteins during their synthesis. However, the disease only damages the peripheral nervous system, the nerves of the hands and feet, and this is a real mystery.
Again, this process occurs in all cells, so why should hands and feet be affected more? The new study offers the answer: GlyRS has a role outside of protein synthesis. The researchers found that mutations in GlyRS trigger unusual interactions between GlyRS and another enzyme called histone deacetylase-6 (HDAC6). Normally, HDAC6 would regulate a process called acetylation, which prepares a protein called α-tubulin for its role in microtubule formation. These cellular structures are comparable to highways. Thanks to α-tubulin, signaling proteins and other important molecules can compress themselves, sending signals from the tips of the feet to the brain. But in CMT, aberrant protein interactions with HDAC6 prevent the proper acetylation of alpha-tubulin, turning “the highway into a country road”. The signals of the nervous system can not function smoothly and the nerve is longer, the more the road is bumpy. Because our longest nerves reach our feet and our hands, this result explains why CMT2D is more severe in the peripheral nervous system, even if the mutant proteins are present in the body.
Further experiments on a mouse model of CMT2D have shown that researchers could report proper nerve function by injecting mice with a small inhibitor that blocks HDAC6 from interfering with α-tubulin acetylation. Although this particular small molecule is not safe for humans, the team believes that a similar molecule can function as a future therapy for CMT2D. Drs Yang and Mo are thrilled to find this potential treatment goal, but their ultimate goal is to treat the root cause of all types of CMT. To do this, they need to do more studies like this, which reveal the fundamental pathology of the disease. From patient to patient, several mutations can cause mild or very severe symptoms. Some types of CMT are diagnosed in early childhood, while others do not appear until adolescence and this variability displaces all of them. Now that researchers are familiar with this GlyRS interaction with HDAC6, they would like to investigate where other mutant proteins in CMT are causing problems.
In fact, a previous study from the Yang laboratory came across another problem caused by mutant proteins, which has something to do with the nerve maintenance signal. So the picture is much more complicated than what you see and certainly will not fail to reserve surprises and opportunities to develop targeted therapies.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Mo Z et al., Yang XL. Nat Commun. 2018 Mar; 9(1):1007.
He W et al., Yang XL. Nature. 2015; 526(7575):710-4.
Grice SJ et al. Hum Mol Genet. 2015; 24(15):4397-406.
Seburn KL et al. Neuron 2006 Sep 21; 51(6):715-26.
Dott. Gianfrancesco Cormaci
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