Abstract
Myelin is a dynamic membrane that is important for coordinating the fast propagation of action potentials along small or large caliber axons (0.1–10 μm) some of which extend the entire length of the spinal cord. Due to the heterogeneity of electrical and energy demands of the variable neuronal populations, the axo-myelinic and axo-glial interactions that regulate the biophysical properties of myelinated axons also vary in terms of molecular interactions at the membrane interfaces. An important topic of debate in neuroscience is how myelin is maintained and modified under neuronal control and how disruption of this control (due to disease or injury) can initiate and/or propagate neurodegeneration. One of the key molecular signaling cascades that have been investigated in the context of neural injury over the past two decades involves the myelin-associated inhibitory factors (MAIFs) that interact with Nogo receptor 1 (NgR1). Chief among the MAIF superfamily of molecules is a reticulon family protein, Nogo-A, that is established as a potent inhibitor of neurite sprouting and axon regeneration. However, an understated role for NgR1 is its ability to control axo-myelin interactions and Nogo-A specific ligand binding. These interactions may occur at axo-dendritic and axo-glial synapses regulating their functional and dynamic membrane domains. The current review provides a comprehensive analysis of how neuronal NgR1 can regulate myelin thickness and plasticity under normal and disease conditions. Specifically, we discuss how NgR1 plays an important role in regulating paranodal and juxtaparanodal domains through specific signal transduction cascades that are important for microdomain molecular architecture and action potential propagation. Potential therapeutics designed to target NgR1-dependent signaling during disease are being developed in animal models since interference with the involvement of the receptor may facilitate neurological recovery. Hence, the regulatory role played by NgR1 in the axo-myelinic interface is an important research field of clinical significance that requires comprehensive investigation.
Highlights
Central nervous system (CNS) myelination is a developmentally regulated process governed by key molecular events that integrate dynamic changes at axonal and oligodendroglial cell membranes
How Nogo receptor 1 (NgR1) regulates the distribution of contactin associated protein (Caspr) in a tightly orchestrated paranodal interaction with its glial membrane proteins that are integral to the synchrony of axonal myelin physiology is an important question
Future research should involve investigations into CNS remyelination in adult ngr1−/− mice where specific demyelinating lesions are observed during the repair
Summary
Central nervous system (CNS) myelination is a developmentally regulated process governed by key molecular events that integrate dynamic changes at axonal and oligodendroglial cell membranes. We have recently reported that ngr1−/− mice exhibit a sustained expansion of microglia without neuroinflammatory challenge and these cells exhibit increased levels of engulfed myelin proteins (Alrehaili et al, 2018) This observation is consistent with the different expression patterns of Nogo-A found along with the axo-glial units in the spinal cords of ngr1−/− mice, as mice deficient in Nogo-A exhibited faster remyelination upon lysolecithin-induced demyelination when compared to wild-type (Chong et al, 2012). Another open question is whether this endogenous activity, innate to ngr1−/− CNS tissues, is a consequence of potentiated clearance of unstructured myelin. This possibility warrants further investigation as it may provide a further understanding of myelin dynamics during disease and possibly aging
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