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In a Mouse Model, Researchers Restore Myelination in Congenital Hypomyelinating Neuropathy

Talan, Jamie

doi: 10.1097/
At the Bench
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In a mouse model of congenital hypomyelinating neuropathy, investigators bred animals with an MPZ mutation that leads to congenital hypomyelinating neuropathy with another transgenic mouse that overexpresses neuregulin 1 type III. They found that the gene therapy approach improved symptoms and promoted myelination in both the peripheral and central nervous systems.

Overexpressing the axonal protein neuregulin 1 type III increases the thickness of the myelin sheath and leads to restored myelination, as well as improvements in cell-to-cell signaling and functioning in animals with pathological features of congenital hypomyelinating neuropathy (CHN).

CHN, a rare myelin disorder diagnosed in infancy, causes muscle weakness and low muscle tone, leading to neuropathy. The babies produce very small amounts of myelin.

Studies have shown that CHN is caused by mutations in two genes: myelin protein zero (MPZ) and early growth response gene-2 (EGR2). Both genes make myelin to insulate nerve cells. MPZ encodes for a protein called P0 that allows for the formation and stability of myelin in the peripheral nervous system. Mutations cause a reduction in myelin thickness. EGR2 makes a protein that stimulates the production of myelin.

The hope is that the delivery of a protein that modulates neuregulin 1 type III in neurons in the peripheral nervous system could be used to increase myelin thickness in patients with diseases that result in myelin damage.

“If we can manipulate myelin thickness, it opens up the opportunity to treat other more common conditions like Charcot-Marie-Tooth disease and Guillain-Barré syndrome,” said Yannick Poitelon, PhD, assistant professor in the neuroscience and experimental therapeutics program at Albany Medical College and a co-author of the study, published online December 10 in Human Molecular Genetics.

“The study led to some surprising findings that we are now trying to understand,” added Sophie Belin, PhD, a research associate in Dr. Poitelon's lab and first author of the study. Dr. Belin has been studying peripheral myelinating diseases at the University of Buffalo, where she continued her postdoctoral training under Lawrence Wrabetz, MD, director of the Hunter James Kelly Research Institute and professor of neurology and biochemistry at the University of Buffalo. Dr. Wrabetz is senior author of the current study.

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Study Methods, Findings

The mouse model, developed in the Wrabetz lab, mimics CHN pathology. The myelin is too thin, and as a result the nerve conduction velocity is reduced. Dr. Belin has been using the animal model to determine ways to increase the thickness of myelin.

To that end, the scientists designed a genetic approach to see if it would activate more myelin during development and reduce the CHN pathology. They decided to breed animals with an MPZ mutation that leads to CHN with another transgenic mouse that overexpresses neuregulin 1 type III. This protein is known to activate more myelin in both the peripheral and central nervous systems. (The scientists only wanted activation in the periphery.)

They asked: Can the newly bred mice that have both reduced expression of P0 and overexpression of neuregulin 1 type III recover from the MPZ genetic mutation? To assess this, they looked at the pathology at the sciatic nerve, observing the quality of the myelin lining and its thickness. They measured nerve conduction velocity of the signals coming in and going out of the sciatic nerve. Finally, they wanted to observe if the mice were walking better.

“The results were encouraging,” said Dr. Belin. “We saw a functional improvement in how the animals moved about, and we saw improvements in velocity.”

Still, the researchers had more questions: Were the animals really forming more myelin? Was the myelin normal? To understand which pathways were activated, the scientists looked at gene expression. Normally myelin is formed by Schwann cells. Glial cells wrap around the axons and allow for nerve conduction to muscles. The research team could see that this specific signaling pathway in Schwann cells was activated.

But when they looked at protein levels in the sciatic nerves (compared with control animals) the composition was not what they expected to find with the increased myelin thickness. In fact, they discovered they were generating an alternative myelin product. This myelin protein normally controls cholesterol trafficking and is not the myelin that insulates axons. Changing the component of the material, they were able to increase myelin thickness, and the animal's ability to walk improved.

This was promising. There was a problem, however: While neuregulin 1 type III was active in the periphery, it was also making its mark in the central nervous system, and that was having harmful effects on brain function. (In humans, high levels of neuregulin 1 type III have been found in patients with schizophrenia and Alzheimer's.)

“We have to be very careful,” explained Dr. Belin. “We need a substance that targets only the periphery. The findings are promising, but we need to find another way to increase myelin thickness only in the periphery.”

“The improvement was independent from the upregulation of EGR2 or essential myelin genes,” the study authors explained in the paper. “Rather, we observed the activation of MAPK/ERK and other myelin genes such as peripheral myelin protein 2 (PMP2) and oligodendrocyte myelin glycoprotein (OMG).”

The research team is now focusing their next experiments on PMP2. This protein, expressed in the Schwann cells of the peripheral nervous system, helps with cholesterol binding.

“We believe that regulating the level of lipids can increase the thickness of myelin, and this would be specific for the peripheral nervous system,” explained Dr. Poitelon. The team is now creating Pmp2 knockouts to understand the effects of the protein.

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Expert Commentary

“The research team took a mouse engineered to overexpress neuregulin 1 type III, and they showed that this results in a thicker myelin,” explained Michael E. Shy, MD, director of the division of neuromuscular medicine and professor of neurology, pediatrics, molecular physiology, and biophysics at the University of Iowa. “They showed that it leads to increased expression of a specific myelin protein called Pmp2. This suggests that a separate signaling pathway may be involved in their study, a pathway that is important in lipid and cholesterol regulation, which is also involved in myelin formation.”

Dr. Shy added, “Myelin nerve fibers in the peripheral nervous system come in different sizes, and the main effects are in the smaller myelinated axons, not the larger ones. Functionally, it makes the mice a little better.”

“Whether this will be useful in all myelin diseases is just not known,” he said. “To use neuregulin 1 type III in patients with these conditions would require targeting of only nerve cells in the peripheral nervous system, which is an issue because neuregulin 1 type III is also expressed in the central nervous system, where it regulates gene expression in oligodendrocytes.”

“In general, the principle of ameliorating neuropathies by targeting key signals/signaling pathways is highly appealing and was always in the background with older neuregulin studies,” said James Salzer, MD, PhD, professor of cell biology, neurology, and neuroscience at NYU School of Medicine. “But neuregulin itself has effects on many tissues, so may have too many off-target effects to be used as a primary agent.”

The advance is promising, the independent experts agreed, but more research is needed.

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Drs. Belin and Poitelon reported no relevant disclosures.

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Link Up for More Information

•. Belin S, Ornaghi F, Shackleford G, et al Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy Human Mol Genet 2018; Epub 2018 Dec 10.
    © 2019 American Academy of Neurology