Study finds new molecular mechanism involved in myelin repair

A protein called Daam2 helps to regulate the activity of cells in the brain that make myelin, the fatty covering around nerve fibers that’s damaged in multiple sclerosis (MS), a new study shows.

By uncovering how that protein functions in the brain to boost myelin repair, researchers have discovered new approaches that could be explored for the development of novel MS treatments.

“This study opens exciting therapeutic avenues we could develop in the future to repair and restore myelin, which has the potential to alleviate and treat several neurological [diseases] that are currently untreatable,” Hyun Kyoung Lee, PhD, a professor at Baylor College of Medicine and co-author of the study, said in a press release.

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The study, “Daam2 phosphorylation by CK2[alpha] negatively regulates Wnt activity during white matter development and injury,” was published in PNAS.

Multiple sclerosis is caused by inflammation in the brain and spinal cord that damages myelin — a fatty substance that wraps around nerve fibers like a sheath and helps them send electrical signals. This damage interferes with normal nerve signaling, which ultimately gives rise to MS symptoms.

Myelin in the brain is made mainly by cells called oligodendrocytes. The molecular mechanisms that regulate oligodendrocyte activity remain incompletely understood, but better insight into these mechanisms may open doors toward treatments to promote myelin repair.

In this study, scientists at the Baylor College of Medicine and Texas Children’s Hospital used experiments in cell and animal models to deduce one part of the molecular machinery that regulates oligodendrocyte activity.

Study focused on the Daam2 protein

The study focused on a protein known as Daam2 (short for dishevelled-associated activator of morphogenesis 2). This protein is known to be involved in the Wnt pathway, which is a molecular pathway that is critical for regulating the development of oligodendrocytes.

Daam2 levels and Wnt activity both are increased in oligodendrocytes near MS-related damage, suggesting that increased activity in these pathways may reduce myelin repair.

Normally, the Daam2 protein helps to block the activity of another complex of proteins that can function to turn off the Wnt pathway. The researchers determined that Daam2 is able to undergo a type of chemical modification called phosphorylation, and when Daam2 undergoes this modification it no longer is able to stop this other complex. As a result, when Daam2 becomes phosphorylated, Wnt activity decreases.

The researchers figured out that another protein, CK2-alpha, is responsible for controlling whether Daam2 is phosphorylated. Taken together, these data  suggest a molecular mechanism where CK2-alpha can control whether or not the Wnt pathway is active by phosphorylating Daam2.

“Overall, our findings suggest that the CK2[alpha]–Daam2 pathway plays a crucial role in the regulation of [oligodendrocyte] biology and pathology associated with Wnt signaling,” the researchers wrote.

The scientists showed this pathway helps to control the development of oligodendrocytes over time. Under normal conditions, Daam2 is not phosphorylated in early oligodendrocyte development, so Wnt is active, which helps the cell mature. Then, as the cell matures, CK2-alpha becomes activated to phosphorylate Daam2, which stops Wnt activation.

Improvements in myelin repair

In a mouse model that mimics myelin loss in MS, engineering mice to express more phosphorylated Daam2 led to improvements in myelin repair, suggesting that targeting Daam2 to turn off Wnt signaling may help spur oligodendrocytes to fix damaged myelin.

The researchers stressed that more work is needed to understand these molecular mechanisms more fully, but they speculated these processes may be useful treatment targets to promote myelin repair in MS.