Scientists find roadblock that stops myelin repair

May 09, 2018
A new study identifies a molecule that may be critical to the repair of myelin, the fatty tissue wrapped around parts of brain cells that helps speed up communication. New findings suggest that the molecule triggers a pathway that is normally used by the immune system to prevent excessive damage, but may contribute to chronic white matter injury by completely blocking repair operations.
Myelin is formed by oligodendrocytes, specialized cells that come from developing cells called oligodendrocyte progenitor cells. Studies have shown that in cases of chronic white matter injury, OPCs accumulate in the lesions, ready to help, but for some reason are not able to produce myelin. A very large molecule called hyaluronic acid also accumulates in the lesions and is broken down into small fragments that are thought to prevent OPCs from producing myelin.
Researchers at the Oregon Health and Science University in Portland, Ore., took a detailed look at the HA fragments to see how they block myelin repair. They were able to create HA fragments of different sizes. Results showed that only one specific size of HA, the 210 kDa fragment, had an effect on OPC proliferation.
The team treated rat cells that mimicked white matter disease with the 210 kDa HA fragment. They discovered that the HA initially turned on molecules linked to myelination, but then shut them down completely. It’s a strategy that is similar to immune tolerance, which is used by the immune system to prevent severe tissue injury from an ongoing, damaging response to bacteria and viruses.
The study’s authors also discovered that the 210 kDa fragment signals to TLR4, a protein that oversees immune tolerance, to activate FoxO3, which helps control the activity of genes involved in myelin repair. This activation of FoxO3 eventually leads to a decrease in the activity of myelin-related genes and a slowdown in white matter repair. However, this process only takes place if HA is present.
When they looked at human brain tissue affected by white matter injury and multiple sclerosis, they found activated FoxO3 in OPCs that were blocked from producing myelin.
In the brain, the large, intact HA makes up most of the extracellular matrix, which is the substance found between cells. Damage to the extracellular matrix leads to inflammation and this can occur in white matter injury.
The authors note that more research is needed to learn about the molecules involved in white matter repair as well as the role of different HA fragments in these processes.
The study, published in the May issue of Journal of Clinical Investigation.

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