New clues to MS nerve damage

Scientists have found a “missing link” in the treatment of multiple sclerosis (MS), the Daily Mirror has reported. The newspaper said that new research has identified a new molecule “that could lead to a drug treatment to repair the damage caused by the disease”.

The study used human brain tissue and mice to explore the function of cells called oligodendrocytes. These cells make myelin sheaths, the fatty structures that surround nerve cells and help them send their signals more effectively. Damage or loss of these sheaths, which happens in multiple sclerosis, hampers the ability of the brain to send signals correctly, and leads to symptoms such as difficulty controlling the body’s movement.

In their experiments, the researchers identified that a protein, called Axin2, plays an important role in the development of myelin-making cells. They also identified a chemical that can stabilise levels of Axin2 and accelerate the repair of damaged myelin sheaths in mice.

More animal research will now be needed to determine whether the chemical used in this study, or similar chemicals, appear to be effective and safe enough for tests in humans. Such research takes time, and not all chemicals that initially show promise are effective or safe in humans. However, the finding offers a new avenue of exploration for potential treatments for diseases such as MS.

Where did the story come from?

The study was carried out by researchers from the University of California, Stanford University and the University of Cambridge. It was funded by the US National Multiple Sclerosis Society, the UK Multiple Sclerosis Society, the US National Institutes of Health and the University of California.
The study was published in the peer-reviewed scientific journal Nature Neuroscience.

In its report, the Daily Mirror did not state that the research took place in the laboratory and animals, but it did note that any new treatments for MS might be another 10 to 15 years away.

What kind of research was this?

This laboratory and animal study looked at the role of a protein called Axin2 in the development of the myelin sheath, a protective membrane wrapped around some nerve cells.

Myelin sheaths are layers of a fatty substance that wrap around the axons, the long structures that nerve cells use to transmit their signals to each other and other tissues. The sheaths “insulate” the nerves, and help them to transmit signals more quickly. These sheaths and the axons they protect make up the white matter of the brain, while the bodies of the nerve cells make up the grey matter. The myelin sheaths are made by specialised cells called oligodendrocytes.

Damage to the myelin sheaths plays an important role in a number of conditions. For example, if the white matter is damaged during foetal development (as might occur if the brain is starved of oxygen), it can lead to a complex group of movement and co-ordination disorders which fall under the broad term of cerebral palsy. In multiple sclerosis, the body’s immune system attacks the myelin-producing oligodendrocytes, causing loss of the myelin sheaths and neurological symptoms.

If they are damaged, the myelin sheaths can be regenerated by oligodendrocyte progenitor cells (OPCs). However, in damaged white matter, some OPCs appear to “stall” in their development, and fail to progress to the myelin-making stage. This study investigated the Axin2 protein, which the researchers thought might influence the development of OPCs into oligodendrocytes.

What did the research involve?

First, the researchers looked at whether the human gene that produces Axin2 (called AXIN2) was active in OPCs in damaged brain tissue. They compared this to the activity in undamaged brain tissue from human newborns, which provided a control group. They also looked at whether AXIN2 was active in human active multiple sclerosis lesions (areas of white matter damage where there is ongoing inflammation).

The researchers genetically engineered mice in a way that allowed them to identify cells in which the AXIN2 gene was active during development. They also genetically engineered mice to lack the AXIN2 gene in order to determine what effect this had on oligodendrocytes. They then treated these mice and normal mice with a chemical that kills oligodendrocytes, and compared the response of their OPCs.

Finally, they tested the effects of a chemical called XAV939, which they thought might stabilise levels of the Axin2 protein. They tested whether it had this effect on OPC cells in the laboratory. They then tested what effect it had on slices of mouse brain which had been starved of oxygen or exposed to a chemical that reduces myelination of the nerves. Mice whose spinal cords had been damaged with the demyelinating chemical were treated with XAV939, and the researchers looked at the effects.

What were the basic results?

The researchers found that the AXIN2 gene was active in the oligodendrocyte progenitor cells (OPCs) in damaged newborn brain tissue, but not undamaged newborn brain tissue. They also found that the AXIN2 gene was active in the OPCs in active multiple sclerosis lesions, but not in white matter that appeared normal.

In mice, they found that the AXIN2 gene was active in immature OPCs, but not fully mature oligodendrocytes. They also found that mice lacking the AXIN2 gene had slower development of the OPCs. Normal adult mice treated with a chemical that kills oligodendrocytes showed new OPCs with active AXIN2 in the damaged area by ten days after the injury. When this experiment was repeated in mice lacking AXIN2, the oligodendrocyte cells regenerated after the injury but remyelination was delayed compared to normal mice.

The researchers found that the chemical XAV939 stabilised levels of Axin2 in OPCs in the laboratory. Slices of mouse brain in the laboratory, which had been starved of oxygen or exposed to a demyelinating chemical, showed reduced levels of myelin. Treating these slices of brain with XAV939 reversed this effect.

In mice whose spinal cords had been treated with a demyelinating chemical, XAV939 increased the number of oligodendrocytes in the injured areas. It did this by increasing the rate at which OPCs developed into mature oligodendrocytes and were able to remyelinate the nerves.

How did the researchers interpret the results?

The researchers concluded that the AXIN2 gene is “an essential regulator of remyelination”. They also said that it could serve as a target for drugs and could be manipulated to accelerate this process.

Conclusion

This research used several techniques to explore how a protein called Axin2 is involved in the development of oligodendrocyte cells from oligodendrocyte progenitor cells. Oligodendrocytes produce myelin sheaths that surround nerve cells and help them transmit their signals more effectively. The study also found that a chemical called XAV939 can accelerate the repair of damaged myelin sheaths in mice with spinal cord lesions.

This type of animal and cellular research is crucial for understanding the biology of disease, and can identify chemicals that may be worth testing in humans. More animal research will be needed to determine whether the chemical used in this study or similar chemicals appear to be effective and safe enough for testing in human trials. Such research takes time, and not all chemicals that show promise in animals are effective or safe in humans. However, the finding offers a new avenue of exploration for potential treatments for diseases such as MS.