Abstract

The myelination of axons by oligodendrocytes is a highly complex cell-to-cell interaction. Oligodendrocytes and axons have a reciprocal signaling relationship in which oligodendrocytes receive cues from axons that direct their myelination, and oligodendrocytes subsequently shape axonal structure and conduction. Oligodendrocytes are necessary for the maturation of excitatory domains on the axon including nodes of Ranvier, help buffer potassium, and support neuronal energy metabolism. Disruption of the oligodendrocyte-axon unit in traumatic injuries, Alzheimer’s disease and demyelinating diseases such as multiple sclerosis results in axonal dysfunction and can culminate in neurodegeneration. In this review, we discuss the mechanisms by which demyelination and loss of oligodendrocytes compromise axons. We highlight the intra-axonal cascades initiated by demyelination that can result in irreversible axonal damage. Both the restoration of oligodendrocyte myelination or neuroprotective therapies targeting these intra-axonal cascades are likely to have therapeutic potential in disorders in which oligodendrocyte support of axons is disrupted.

Highlights

  • Structural variants of the myelin sheath have arisen several times during evolution as a means to allow for the rapid conduction of nerve impulses along axons, including in vertebrates and some species of worm and shrimp (Roots, 2008)

  • We focus on recent advances in our understanding of the cellular mechanisms by which oligodendrocytes support axonal and neuronal integrity, how neurons adapt to demyelination, and the intra-axonal cascades contributing to their degeneration

  • Given numerous clinical trials are beginning with the aim of improving remyelination, it will be crucial to determine whether remyelinating oligodendrocytes provide long-term support of axonal health and how they differ from those produced during development

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Summary

Introduction

Structural variants of the myelin sheath have arisen several times during evolution as a means to allow for the rapid conduction of nerve impulses along axons, including in vertebrates and some species of worm and shrimp (Roots, 2008). The susceptibility of axons to damage following myelin and oligodendrocyte loss is observed in other demyelinating pathologies as well. Given oligodendrocytes do not store glycogen, this suggests a mechanism by which this oligodendroglial uptake of glucose and subsequent supply of glycolysis products might be matched to levels of activity in the myelinated axons (Micu et al, 2016), supporting axons during times of heightened metabolic load (Micu et al, 2017).

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