Neuroprotection by central nervous system remyelination: Molecular, cellular, and functional considerations - PubMed (original) (raw)

Review

. 2016 Dec;94(12):1411-1420.

doi: 10.1002/jnr.23923. Epub 2016 Sep 12.

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Review

Neuroprotection by central nervous system remyelination: Molecular, cellular, and functional considerations

Dylan Verden et al. J Neurosci Res. 2016 Dec.

Abstract

Oligodendrocytes and their myelin sheaths play an intricate role in axonal health and function. The prevalence of white matter pathology in a wide variety of central nervous system disorders has gained attention in recent years. Remyelination has therefore become a major target of therapeutic research, with the aim of protecting axons from further damage. The axon-myelin unit is elaborate, and demyelination causes profound changes in axonal molecular domains, signal transmission, and metabolism. Remyelination is known to restore some of these changes, but many of its outcomes remain unknown. Understanding how different aspects of the axon-myelin unit are restored by remyelination is important for making effective, targeted therapeutics for white matter dysfunction. Additionally, understanding how subtle deficits relate to axonal function during demyelination and remyelination may provide clues into the impact of myelin on neuronal circuits. In this review, we discuss the current knowledge of the neuroprotective effects of remyelination, as well as gaps in our knowledge. Finally, we propose systems with unique myelin profiles that may serve as useful models for investigating remyelination efficacy. © 2016 Wiley Periodicals, Inc.

Keywords: axon; demyelination; oligodendrocytes.

© 2016 Wiley Periodicals, Inc.

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Conflict of interest statement

Conflict of Interest: The authors declare no known conflict of interest.

Figures

Figure 1:

Figure 1:. Nodal alterations following demyelination and remyelination.

Healthy axo-myelin units are displayed on the left of each panel for comparison. A: In healthy myelinated axons, voltage-gated sodium channels (Nav1.6, blue) are located at the node of Ranvier, while voltage-gated potassium channels (Kv1.1,2, orange), ATP-dependent Na+/K+ pumps (yellow), and mitochondria localize to the juxtaparanode. Inward-rectifying K+ channels (Kir4.1, red) are expressed by both oligodendrocytes and astrocytes, which extend perinodal processes that contribute to node function. Different monocarboxylate transporters (MCTs) are expressed by oligodendrocytes (MCT1, pink), axons (MCT2, blue), and astrocytes (MCT4, brown), indicating an important role for lactate metabolism. B: Loss of paranodal junctions (purple) due to demyelination results in Kv channel diffusion along the axolemma. Nav clusters also diffuse, and axons begin expressing Nav1.2 along the former internode. This increases the area across which ion gradients must be maintained, causing broad expression of Na+/K+ pumps and increasing mitochondrial density to meet axonal energy demands. Axonal MCT expression is reduced, potentially to compensate for high extracellular lactate levels. C: Following remyelination, ion channel and pump localization is restored, with some Kv channels persisting in the paranodal region. Mitochondrial density remains elevated, while the expression of MCTs during this period is unknown. Notably, the presence or absence of perinodal astrocyte processes during demyelination and remyelination has yet to be elucidated. Other morphological factors of remyelinated axons, such as the size of the periaxonal space, also remain unknown.

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