Novel Mechanism for Myelin Regeneration Uncovered: Implications for Neurological Disorders

A groundbreaking study led by Dr. Hyun Kyoung Lee, an associate professor at Baylor College of Medicine and a researcher at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, has illuminated a previously unidentified biological process that facilitates the repair and regrowth of myelin. Myelin is the protective sheath around nerve fibers essential for efficient neural signal transmission.

The research team at Duncan NRI has shed light on the unique roles played by the Dishevelled associated activator of morphogenesis 2 (Daam2) protein and CK2α kinase in regulating the restoration and regrowth of myelin. This study has been formally documented in the Proceedings of the National Academy of Science.

Myelin is synthesized by a category of glial precursor cells known as oligodendrocytes (OLs), which are abundant in the nervous system. A compromised myelin sheath is a defining characteristic of various neurological conditions affecting both adults, such as multiple sclerosis, and infants, like cerebral palsy, and is often observed following traumatic brain injuries.

The Wingless (Wnt) signaling pathway has been identified as a pivotal regulator in OL development and myelin regeneration. Under diseased states or following a brain injury, elevated levels of this pathway in the brain’s white matter hinder myelin production by causing oligodendrocytes to enter a dormant or “stalled” state.

Several years ago, Dr. Lee and her colleagues established that Daam2, a glial protein, impedes the differentiation of oligodendrocytes and, subsequently, the repair and regrowth of myelin. However, the specific mechanisms by which this occurs have remained elusive until now.

To comprehend how Daam2 obstructs myelin formation, the researchers first had to understand Daam2’s regulation. Employing biochemical methods, they ascertained that two amino acid residues of the Daam2 protein are phosphorylated, a commonly occurring post-translational adjustment that activates or deactivates proteins.

The research team then examined the effects of Daam2 phosphorylation on OL lineage progression by evaluating differentially expressed genes (DEGs) in both wild-type and mutant animals with permanently phosphorylated Daam2. They discovered that DEGs in mutant OLs were involved in lipid and cholesterol metabolism as well as multiple signaling mechanisms, including the Wnt pathway.

Further investigation confirmed the involvement of CK2, a Wnt/β-catenin signaling Ser/Thr kinase, in Daam2 phosphorylation. Through biochemical and genetic screens, they identified its catalytic subunit, CK2α, as interacting with Daam2 in lab-cultured OLs and also as being responsible for its phosphorylation.

Moreover, experimental results from both in vitro cultured OLs and in vivo mouse models presented compelling evidence that CK2α influences OL differentiation by phosphorylating Daam2. Subsequent studies utilizing an animal model of neonatal hypoxic injury revealed a beneficial role for CK2α-mediated Daam2 phosphorylation in developmental and behavioral recovery post-neonatal hypoxia, a type of brain injury commonly seen in conditions like cerebral palsy.

Collectively, these insights have disclosed a new regulatory point in the Wnt signaling pathway that controls stage-specific development of oligodendrocytes and opens avenues for novel biological techniques to regenerate myelin.

Dr. Lee stated, “This research heralds promising therapeutic pathways for the future, potentially allowing for the repair and regeneration of myelin, thereby addressing various untreatable neurological conditions.”

Reference: The study, dated 22 August 2023, was authored by Chih-Yen Wang, now an assistant professor at the National Cheng Kung University, and several other researchers affiliated with Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital. The study received financial support from multiple sources including NIH/NINDS, the National Multiple Sclerosis Society, and various endowments.

Neurological Research, Myelin Repair, Multiple Sclerosis, Cerebral Palsy, Wnt Signaling Pathway, Oligodendrocytes, Daam2 Protein, CK2α Kinase, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute