Charcot-Marie-Tooth disease is a little-known, yet relatively common, inherited neurological condition that affects an estimated 150,000 people in the U.S., according to the National Institutes of Health. It typically causes weakness, numbness, muscle cramps and movement problems in legs and arms. The CMT type 2A form of the disease also may cause wasting of the optic nerve, spinal cord damage leading to difficulty walking, hearing loss, developmental delay and changes in vital tissues of the brain known as white matter.
A recent study in the Journal of Clinical Investigation provides critical insight and points to possible treatments for this disease and better understanding of other neurodegenerative disorders, including Alzheimer's disease. The study focused on two related proteins - MFN2 and MFN1 - found on the outer membranes of mitochondria, which are structures inside the body's cells that convert food into energy.
Previous research has shown that mutated MFN2 causes mitochondria to malfunction in a common type of Charcot-Marie-Tooth disease - CMT type 2A. The study showed that increasing levels of MFN1 to counterbalance mutated MFN2 reduced symptoms of CMT type 2A and neurodegeneration in laboratory mice. Despite the fact that mutated MFN2 can be expressed in every cell in the body, CMT type 2A primarily affects the nervous system. This is because levels of MFN1 are particularly low in brain cells, and restoring those levels can improve mitochondrial function. “That fact is significant because findings about CMT2A can go beyond just a single disease,” says Robert Baloh, MD, Ph.D., and professor of Neurology. “The hope is that similarly increasing MFN1 potentially could treat other neurodegenerative diseases that also involve mitochondrial dysfunction.
Previous laboratory studies showed that the protein MFN1 could compensate for the loss of function of mutated MFN2. The new study advances these findings by testing the approach in laboratory mice. To perform this experiment, the investigators incorporated a human gene with the mutation that causes the disease into the genome of the mouse. This technique allowed them to study CMT type 2A over the lifetime of the lab animal. Mice with the mutated gene developed symptoms of CMT type 2A. When levels of MFN1 or normal MFN2 were increased in mice with CMT type 2A, the disease process almost completely stopped. It appears that MFN1 helps take over the work of the disabled, mutated protein in mice.
Zeroing In On A Treatment
About one in 2,500 people have Charcot-Marie-Tooth. Scientists at The Scripps Research Institute have shown a path to developing treatments for disease subtype CMT2D and it may be possible to reverse the disease by using a small molecule to restore normal protein function in the nervous system. The study - reported in the journal Nature Communications - 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, but 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.
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 ?-tubulin for its role in forming microtubules. Because of ?-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 ?-tubulin acetylation, turning that highway into a dirt 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 ?-tubulin acetylation. Although this particular small molecule would not be safe for humans to take, a similar molecule may work as a future CMT2D therapy. 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. 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. The researchers hope future studies can solve these mysteries and even show a way to target mutant GlyRS itself. The researchers 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.
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With over 30 years of writing and editing experience for newspapers, magazines and corporate communications, Kevin Kerfoot writes about natural health, nutrition, skincare and oral hygiene for Trusted Health Products’ natural health blog and newsletters.
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