Scientists zero in on treatment for Charcot-Marie-Tooth disease

March 8, 2018, The Scripps Research Institute
Xiang-Lei Yang, PhD, and Zhongying Mo, PhD, led the study at The Scripps Research Institute. Credit: Cindy Brauer

About 1 in 2,500 people have a degenerative nerve disease called Charcot-Marie-Tooth (CMT). The disease is typically diagnosed in children, who can lose their ability to walk and use their hands for fine motor skills. There is no cure—yet.

Scientists at The Scripps Research Institute (TSRI) have now shown a path to developing treatments for disease subtype CMT2D. As they report in the journal Nature Communications, it may be possible to reverse the disease by using a small molecule to restore normal function in the nervous system.

"This study provides guidance for developing therapeutics," says Xiang-Lei Yang, PhD, TSRI professor and senior author of the study.

Importantly, the study reveals how a better understanding of the fundamental causes of CMT can point researchers toward a cure for other subtypes.

Detective work reveals new role for mutant protein

Here's a puzzle: 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.

Adding to the mystery, studies show that GlyRS primarily affects a process called protein synthesis, where genetic information is translated into proteins. Again, this process happens in all cells, so why would hands and feet be most affected?

"Our everyday research is like a detective role," says Zhongying Mo, PhD, senior research associate at TSRI and first author of the study.

The new study offers the answer: GlyRS has a role outside .

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. Yang compares microtubules to a highway. Thanks to α-tubulin, signaling proteins and other important molecules can zip along, sending signals from your tiptoes to your brain.

But in CMT, the aberrant protein interactions with HDAC6 prevent proper α-tubulin acetylation, turning that highway into a dirt road. Nervous system signals can't run smoothly, and the longer the nerve, the rougher the road. Because our longest nerves reach our 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 the 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 to take, Yang and Mo believe a similar molecule may work as a future CMT2D therapy.

"It's exciting when you can accumulate all the evidence and point to a specific target," says Mo.

Targeting the root cause of CMT

Yang and Mo are excited to find this potential treatment target, 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 one, which reveal the fundamental pathology of the disease.

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," Yang says.

Now that the researchers know about this GlyRS interaction with HDAC6, they would like to investigate where else mutant proteins in CMT are causing problems. In fact, an earlier study from the Yang lab caught another problem made by the mutant proteins, which has something to do with affecting nerve maintenance signal. Yang hopes future studies can solve these mysteries and even show a way to target mutant GlyRS itself.

"Our understanding of the is ever-increasing," says Yang.

Explore further: Scientists find new cancer drug target in dual-function protein

More information: Zhongying Mo et al, Aberrant GlyRS-HDAC6 interaction linked to axonal transport deficits in Charcot-Marie-Tooth neuropathy, Nature Communications (2018). DOI: 10.1038/s41467-018-03461-z

Related Stories

Scientists find new cancer drug target in dual-function protein

June 27, 2016
Scientists at The Scripps Research Institute (TSRI) have identified a protein that launches cancer growth and appears to contribute to higher mortality in breast cancer patients.

HDAC6 inhibitors protect against neuronal damage and have therapeutic potential in neurology and oncology

February 8, 2018
Inhibiting HDAC6 improves the structural stability of cells and protects against neuronal damage. Leuven research uncovered that targeting this mechanism could be a promising therapeutic approach for peripheral neuropathies, ...

Targeting mutant proteins might be silver bullet for neurodegenerative diseases

October 21, 2015
Scientists have unraveled how mutant molecules damage the nervous system of people with Charcot-Marie-Tooth (CMT) disease, a group of disorders that hinder people's ability to move and feel sensation in their hands and feet, ...

Scientists solve mystery of nerve disease genes

July 4, 2011
For several years, scientists have been pondering a question about a genetic disease called Charcot-Marie-Tooth (CMT) disease type 2D: how can different types of mutations, spread out across a gene, produce the same condition?

Mice point to a therapy for Charcot-Marie-Tooth disease

August 2, 2011
VIB researchers have developed a mouse model for Charcot-Marie-Tooth (CMT) neuropathy, a hereditary disease of the peripheral nervous system. They also found a potential therapy for this incurable disease. The treatment ...

Thwarting abnormal neural development with a new mutation

January 18, 2016
Researchers at the RIKEN Brain Science Institute in Japan have discovered how to reverse the abnormal axonal development characteristic of CFEOM3, a congenital disease that affects the muscles that control eye movements. ...

Recommended for you

Classifying brain microglia: Which are good and which are bad?

December 6, 2018
Microglia are known to be important to brain function. The immune cells have been found to protect the brain from injury and infection and are critical during brain development, helping circuits wire properly. They also seem ...

Friend or foe? Brain area that controls social memory also triggers aggression

December 5, 2018
Columbia scientists have identified a brain region that helps tell an animal when to attack an intruder and when to accept it into its home. This brain area, called CA2, is part of the hippocampus, a larger brain structure ...

How the brain hears and fears

December 5, 2018
How is it that a sound can send a chill down your spine? By observing individual brain cells of mice, scientists at Cold Spring Harbor Laboratory (CSHL) are understanding how a sound can incite fear.

Adding new channels to the brain remote control

December 5, 2018
By enabling super-fast remote control of specific cells, light-activated proteins allow researchers to study the function of individual neurons within a large network—even an entire brain. Now one of the pioneers of 'optogenetics' ...

Microbial-based treatment reverses autism spectrum social deficits in mouse models

December 4, 2018
An unconventional approach has successfully reversed deficits in social behaviors associated with autism spectrum disorders (ASD) in genetic, environmental and idiopathic mouse models of the condition. Researchers at Baylor ...

'Error neurons' play role in how brain processes mistakes

December 4, 2018
New research from Cedars-Sinai has identified neurons that play a role in how people recognize errors they make, a discovery that may have implications for the treatment of conditions including obsessive-compulsive disorder ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.