Researchers have found a brand new organic mechanism involving Daam2 protein and CK2α kinase that regulates myelin restore and regeneration. This research has implications for treating neurological ailments like a number of sclerosis and cerebral palsy.

A research led by Dr. Hyun Kyoung Lee, affiliate professor at Baylor Faculty of Medication and investigator on the Jan and Dan Duncan Neurological Analysis Institute at Texas Youngsters’s Hospital, has recognized a beforehand unknown organic mechanism for repairing and regenerating myelin. Myelin is the insulating layer round nerve fibers that’s essential for the quick and exact transmission of neural indicators.

The Duncan NRI workforce discovered novel roles for the Dishevelled related activator of morphogenesis 2 (Daam2) protein and CK2α kinase in regulating myelin restore and regeneration. The research was not too long ago printed within the Proceedings of the Nationwide Academy of Science.

Myelin is produced by a sort of glial precursor cells known as oligodendrocytes (OLs) that are among the many most quite a few cells within the nervous system. Injury or lack of myelin sheath is the hallmark of assorted neurological ailments in adults (e.g. a number of sclerosis) and infants (e.g. cerebral palsy) and is frequent after mind accidents.

The Wingless (Wnt) signaling pathway is without doubt one of the key regulators of OL growth and myelin regeneration. In sure diseased situations and mind harm, its ranges are elevated within the white matter, which impairs myelin manufacturing by forcing oligodendroctyes to stay in a “stalled/quiescent state”.

A number of years again, Dr. Lee and others discovered {that a} glial protein, Daam2 inhibits the differentiation of oligodendrocytes throughout growth in addition to myelin regeneration and restore. Nevertheless, till now exact mechanisms underlying this course of have remained a thriller.

To know how Daam2 inhibits myelination, the workforce first wanted to find out the regulation of Daam2 itself. Utilizing biochemical approaches, they discovered two amino acid residues (Ser704 and Thr705) of Daam2 protein bear phosphorylation – a standard post-translational regulatory mechanism that activates or off the exercise of the proteins.

To discover if Daam2 phosphorylation affected the development of OL lineage, they analyzed differentially expressed genes (DEGs) in wild-type and mutant animals whose Daam2 is constitutively phosphorylated. DEGs downregulated within the mutant OLs had been enriched in genes concerned in lipid/ldl cholesterol metabolism whereas DEGs upregulated within the mutant OLs had been concerned in a number of signaling processes, together with the Wnt pathway.

Since Daam2 is a identified constructive modulator of canonical Wnt signaling, they examined whether or not these DEGs had been as a result of perturbations in Wnt signaling. They undertook a radical developmental stage-specific evaluation which revealed dynamic adjustments within the equipment and performance of Wnt/β-catenin signaling in early versus late phases of OL growth, and established that this signaling pathway is affected by Daam2 phosphorylation.

“Intriguingly, we discovered Daam2 phosphorylation differentially impacts distinct phases of oligodendrocyte growth – in early phases, it accelerates the conversion of precursor OLs to glial cells however in later phases, it slows down their maturation and their capacity to provide myelin,” Dr. Lee mentioned.

To determine the kinase(s) chargeable for Daam2 phosphorylation, they carried out a motif evaluation which discovered CK2, a Wnt/β-catenin signaling Ser/Thr kinase that was additionally one of many candidates of their biochemical and genetic display screen. They additional confirmed that its catalytic subunit, CK2α, interacted with Daam2 in lab-cultured OLs and in addition phosphorylated it. Furthermore, each Daam2 and CK2α had been sequentially upregulated in a fashion that was concomitant with the development of OL lineage. Utilizing in vitro cultured OLs and in vivo mouse fashions, they discovered compelling proof suggesting that CK2α promotes OL differentiation by phosphorylating Daam2.

Additional research utilizing an animal mannequin of neonatal hypoxic harm mannequin revealed a helpful function for CK2α-mediated Daam2 phosphorylation. They discovered that it performs a protecting function in developmental and behavioral restoration after neonatal hypoxia, a type of mind harm seen in cerebral palsy and different situations, and moreover, it facilitates remyelination after white matter harm in grownup animals.

Collectively, these findings have recognized a novel regulatory node within the Wnt pathway that regulates stage-specific oligodendrocyte growth and presents insights into a brand new organic mechanism to regenerate myelin.

“This research opens thrilling therapeutic avenues we might develop sooner or later to restore and restore myelin, which has the potential to alleviate and deal with a number of neurological which can be at the moment untreatable,” Dr. Lee mentioned.

Reference: “Daam2 phosphorylation by CK2α negatively regulates Wnt exercise throughout white matter growth and harm” by Chih-Yen Wang, Zhongyuan Zuo, Juyeon Jo, Kyoung In Kim, Christine Madamba, Qi Ye, Sung Yun Jung, Hugo J. Bellen and Hyun Kyoung Lee, 22 August 2023, Proceedings of the Nationwide Academy of Sciences.
DOI: 10.1073/pnas.2304112120

The primary writer, Chih-Yen Wang is now an assistant professor within the Nationwide Cheng Kung College. Others concerned within the research had been Zhongyuan Zuo, Juyeon Jo, Kyoung In Kim, Christine Madamba, Qi Ye, Sung Yun Jung, and Hugo J. Bellen. They’re affiliated with a number of of the next establishments: Baylor Faculty of Medication and Jan and Dan Duncan Neurological Analysis Institute at Texas Youngsters’s Hospital. This work was supported by grants from NIH/NINDS, the Nationwide A number of Sclerosis Society, the Cynthia and Anthony G. Petrello Endowment, and the Mark A. Wallace Endowment, the Eunice Kennedy Shriver Nationwide Institute of Baby Well being & Human Improvement of the Nationwide Institutes of Well being for the BCM IDDRC Neurobehavior and Neurovisualization Cores. GERM core at Baylor Faculty of Medication helped with mouse line era, scRNA-sequencing was partially supported by the SCG core and GARP core.