Signalling Remyelination

Luo F, Burke K, Kantor C, Miller RH, Yang Y. Cyclin-Dependent Kinase 5 Mediates Adult OPC Maturation and Myelin Repair through Modulation of Akt and GsK-3β Signaling. J Neurosci. 2014; 34(31):10415-10429.

Failure of remyelination in diseases, such as multiple sclerosis (MS), leads to permanent axonal damage and irreversible functional loss. The mechanisms controlling remyelination are currently poorly understood. Recent studies implicate the cyclin-dependent kinase 5 (Cdk5) in regulating oligodendrocyte (OL) development and myelination in CNS. In this study, we show that Cdk5 is also an important regulator of remyelination. Pharmacological inhibition of Cdk5 inhibits repair of lysolecithin lesions. This inhibition is a consequence of Cdk5 disruption in neural cells because remyelination in slice cultures is blocked by Cdk5 inhibitors, whereas specific deletion of Cdk5 in OLs inhibits myelin repair. In CNP-Cre;Cdk5fl/flconditional knock-out mouse (Cdk5 cKO), myelin repair was delayed significantly in response to focal demyelinating lesions compared with wild-type animals. The lack of myelin repair was reflected in decreased expression of MBP and proteolipid protein and a reduction in the total number of myelinated axons in the lesion. The number of CC1+ cells in the lesion sites was significantly reduced in Cdk5 cKO compared with wild-type animals although the total number of oligodendrocyte lineage cells (Olig2+ cells) was increased, suggesting that Cdk5 loss perturbs the transition of early OL lineage cell into mature OL and subsequent remyelination. The failure of remyelination in Cdk5 cKO animals was associated with a reduction in signaling through the Akt pathway and an enhancement of Gsk-3β signaling pathways. Together, these data suggest that Cdk5 is critical in regulating the transition of adult oligodendrocyte precursor cells to mature OLs that is essential for myelin repair in adult CNS.

Cell division protein kinase 5 is a signalling molecule within the cell involved in many processes including neuronal maturation and plasticity and this causes neural cells to produce factors that stimulate oligodendrocyte function.

Akt, also known as protein kinase B (PKB), is a serine/threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration.
Glycogen synthase kinase 3 is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. GSK-3 has since been identified as a kinase for over forty different proteins in a variety of different pathways.

To understand the signalling pathways you will need to do some reading follow the links, but simply to say yet more knowledge on maturation of repairing cells. Could these be druggable..well yes but because so many cell functions use these molecules there would be a side-effect potential following long-term use however do we need to treat for ever or use short pulses of treatment to trigger repair. Answers to this will influence how useful a therapeutic target these will be

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