Researchers have discovered how the formation of myelin sheaths is regulated by protein molecules. This knowledge could be used to help MS (multipl sclerosis) patients by stimulating the formation of new myelin sheaths after a relapse.

The research group has already identified protein molecules such as 'Sox10' that regulate the formation and preservation of myelin sheaths. Activation of the myelination program requires several transcription factors including Sox10, Olig2, and Nkx2.2.

The aim of the new project was to understand how the identified proteins with the regulating function in the oligodendrocytes interact when myelin is formed. The researchers discovered that other molecules called Nfat proteins are required for this interaction between the known molecules to be successful. These are mainly known for their function in the immune system. The presence of Nfat proteins in the oligodendrocytes ensures that all other required protein molecules can exist together in these cells without displacing each other.

In their work, which has recently been published in the journal Nature Communications, the group demonstrated the precise biochemical mechanisms involved. Inhibition of Nfat proteins adversely affects the capability of oligondendrocytes in rats, mice and also humans to form myelin. There are in fact fewer of these proteins in oligondendrocytes in parts of the brain affected by MS. However, it is still unclear whether this is one of the causes of the damage. 'The interrelationships are very complex', emphasizes the author.

On a molecular level, Nfat proteins cooperate with Sox10 to relieve reciprocal repression of Olig2 and Nkx2.2 as precondition for oligodendroglial differentiation and myelination. As Nfat activity depends on calcium-dependent activation of calcineurin signaling, regulatory network and oligodendroglial differentiation become sensitive to calcium signals.

Up to now, only substances that inhibit the activity of Nfat proteins have been developed, such as Cyclosporin A and Tacrolimus. They are used in medicine mainly to keep the immune system under control and thus prevent organ rejection in transplant patients, for example. An interesting fact is that these patients often suffer from neurological disorders that are caused by myelin sheath loss. The new research suggest that these serious side effects are a direct result of the medication to inhibit Nfat proteins. It is thus extremely important that this medication is improved.

The findings demonstrate the significance of Nfat proteins for myelin formation and open up a new approach for the treatment of neurological disorders that currently have no cure.
 
https://www.fau.eu/2018/04/19/news/research/our-vulnerable-nervous-system-what-affects-its-protective-sheaths/

https://www.nature.com/articles/s41467-018-03336-3