TSRI tightens the noose on CMT

TSRI scientists zero in on treatment for Charcot-Marie-Tooth disease

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LA JOLLA, CA—Scientists at The Scripps Research Institute (TSRI) reported a week ago that they have shown a path to developing treatments for a degenerative nerve disease called Charcot-Marie-Tooth (CMT). The path targets the disease subtype CMT2D. As researchers report in the journal Nature Communications, it may be possible to reverse the disease by using a small molecule to restore normal protein function in the nervous system.
CMT, which is typically diagnosed in children, can cause patients to lose their ability to walk and use their hands for fine motor skills. As of yet, there is no cure.
“This study provides guidance for developing therapeutics,” said Xiang-Lei Yang, PhD, TSRI professor and senior author of the study, which reveals how a better understanding of the fundamental causes of CMT can point researchers toward a cure for other subtypes.
CMT2D is caused by mutations in a protein called GlyRS, which is expressed by cells throughout the body. Yet the disease only damages the peripheral nervous system - the nerves in hands and feet. Studies show that GlyRS primarily affects a process called protein synthesis, where genetic information is translated into proteins. This process happens in all cells, so why hands and feet would be most affected has been so far unknown. The new study offers the answer: GlyRS has a role outside protein synthesis.
“Our everyday research is like a detective role,” said Zhongying Mo, PhD, senior research associate at TSRI and first author of the study.
The researchers discovered that mutations in GlyRS trigger unusual interactions between GlyRS and a protein called HDAC6. Normally HDAC6 would regulate a process called acetylation, which readies a protein called α-tubulin for its role in forming microtubules. But in CMT, the aberrant protein interactions with HDAC6 prevent proper α-tubulin acetylation. Nervous system signals can’t run smoothly, and the longer the nerve is, the more issues those signals have. Because the longest nerves in the human body reach feet and hands, this finding explains why CMT2D is most severe in the peripheral nervous system, even though the mutant proteins are everywhere in the body.
Further experiments in a mouse model of CMT2D showed that researchers could bring back proper nerve function by injecting mice with a small molecule that blocks HDAC6 from interfering in α-tubulin acetylation. Although this particular small molecule would not be safe for humans, Yang and Mo believe a similar molecule might work as a future CMT2D therapy.
“It’s exciting when you can accumulate all the evidence and point to a specific target,” Mo said.
Both Yang and Mo are excited to find this potential treatment target, but their ultimate goal is to treat the root causes of all types of CMT. From patient to patient, different mutations can cause either mild or very severe symptoms. Some types of CMT are diagnosed in infancy, while others don’t appear until adolescence. “That variability is striking,” pointed out Yang.
Now that researchers know about this GlyRS interaction with HDAC6, they want to investigate additional locations where mutant proteins in CMT could be causing problems. In fact, an earlier study from the Yang lab caught another problem, namely that mutant GlyRS can interact with Nrp1 receptors that affect nerve maintenance signal. Yang hopes future studies can solve these mysteries and even show a way to target mutant GlyRS itself. She noted, “Our understanding of the disease is ever-increasing.”
Additional authors of the study, entitled “Aberrant GlyRS-HDAC6 interaction links to axonal transport deficit in Charcot-Marie-Tooth neuropathy,” include Huaqing Liu, Qinghua Hu, Jessica Pham, Na Wei, Ze Liu and Jiadong Zhou of The Scripps Research Institute; Xiaobei Zhao and Xu-Qiao Chen of the University of California, San Diego; Robert W. Burgess of The Jackson Laboratory; Samuel L. Pfaff of the Howard Hughes Medical Institute and the Salk Institute for Biological Studies; C. Thomas Caskey of Baylor College of Medicine; Ge Bai of The Scripps Research Institute and the Salk Institute of Biological Studies; and Chengbiao Wu of the University of California, San Diego, and the Veterans Affairs San Diego Healthcare System.
The study was supported the National Institutes of Health (grants R01 GM088278 and R01 NS054154), the Tau Consortium, The Larry L. Hillblom Foundation and by aTyr Pharma, through an agreement with The Scripps Research Institute.

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