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  • Review Article
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Why does remyelination fail in multiple sclerosis?

Nature Reviews Neuroscience volume 3, pages 705–714 (2002)Cite this article

Key Points

  • Although spontaneous regeneration after central nervous system (CNS) damage is rare, demyelinated CNS axons can undergo remyelination. Remyelination can be very efficient, especially in experimental models. However, in multiple sclerosis (MS) — the most common demyelinating disease of adulthood — remyelination often fails, contributing to clinical deterioration. Devising means by which remyelination can be enhanced or reactivated in MS is a major therapeutic goal that will probably be achieved by understanding how remyelination works and why it fails.

  • Remyelination proceeds in two main stages. The first involves the recruitment of oligodendrocyte progenitor cells (OPCs) by proliferation and possibly migration. The second involves the OPCs engaging demyelinated axons and differentiating into myelin-sheath forming oligodendrocytes. Potentially, remyelination can fail at either of these two stages, both of which become less efficient as a consequence of ageing (which probably contributes to the decline in remyelination efficiency during the course of the disease).

  • Emerging clinical evidence indicates that OPCs might be a target of the disease process; this would have implications for the generation of sufficient OPCs for the recruitment phase. Other histopathological evidence indicates that, in some cases, non-remyelinating lesions are full of OPCs and immature oligodendrocytes that fail to become remyelinating oligodendrocytes, implying a failure of differentiation.

  • What factors govern OPC recruitment and differentiation during remyelination? Developmental studies of myelination have provided valuable clues to the factors that might govern remyelination, although there are differences between the two processes. Nevertheless, developmental studies indicate that many signalling molecules, including growth factors, cytokines and chemokines, neurotransmitters and the extracellular matrix (ECM), are likely to be involved in OPC recruitment; in some instances, supporting evidence has been provided by experimental models of remyelination.

  • Regulators of the differentiation of OPCs into oligodendrocytes include growth factors, ECM, adhesion molecules and the Notch-jagged pathway. Details of the intracellular signalling mechanisms and transcriptional regulation of differentiation have emerged and might provide the basis for pharmacological approaches to manipulating this process. However, the crucial mechanism by which an oligodendrocyte ensheaths axons with a spiral wrap that finally compacts to form the myelin sheath is a fundamental aspect of both myelination and remyelination about which little is known.

  • A picture is emerging of a complex matrix of signals that is required for successful remyelination. This matrix involves a diversity of molecules, fulfilling distinct roles and expressed at critical times during the process. Paradoxically, the inflammatory process that is associated with demyelination might also trigger the cascade of events that creates an environment that promotes remyelination.

  • It is not clear why remyelination fails in MS, but given the complexity of the signalling environment, a hypothesis emerges — the 'dysregulation' hypothesis — in which there is no individual villain of the piece, but rather a breakdown in the regulation of myelination signalling. The future challenge will be to identify the non-redundant trigger factors that create a pro-remyelination environment, and establish whether their manipulation will form the basis of remyelination-enhancing therapies for MS.

Abstract

Multiple sclerosis is a common cause of neurological disability in young adults. The disease is complex — its aetiology is multifactorial and largely unknown; its pathology is heterogeneous; and, clinically, it is difficult to diagnose, manage and treat. However, perhaps its most frustrating aspect is the inadequacy of the healing response of remyelination. This regenerative process generally occurs with great efficiency in experimental models, and sometimes proceeds to completion in multiple sclerosis. But as the disease progresses, the numbers of lesions in which demyelination persists increases, significantly contributing to clinical deterioration. Understanding why remyelination fails is crucial for devising effective methods by which to enhance it.

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Figure 1: Multiple sclerosis pathology.
Figure 2: Remyelination failure due to inadequate differentiation of oligodendrocyte-lineage cells in areas of demyelination.
Figure 3: Remyelination and remyelination failure in multiple sclerosis.
Figure 4: Creating a favourable environment for remyelination.

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Acknowledgements

I am grateful to M. Stidworthy and C. ffrench-Constant for their helpful comments on the manuscript, and to A. Chang and B. Trapp for providing the image in figure 2b.

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  1. Department of Clinical Veterinary Medicine and Cambridge Centre for Brain Repair, University of Cambridge, Madingley Road, Cambridge, CB3 0ES, UK

    Robin J. M. Franklin

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DATABASES

LocusLink

FGF

Gal-C

GGF2

Gtx

Hes5

Id1

Id2

Id4

IGF1

IL-1β

β1 integrin

β2 integrin

β5 integrin

jagged

Mash1

MBP

MOG

MyT1

NG2

Notch1

Olig1

p27

PDGF

PDGF-αR

PLP

PPAR-δ

PSA-NCAM

Sox10

tenascin-C

tenascin-R

TGF-β1

TNF-α

TRβ1

vitronectin

OMIM

multiple sclerosis

FURTHER INFORMATION

Encyclopedia of Life Sciences

axons

myelin and action potential propagation

oligodendrocytes

Glossary

SALTATORY CONDUCTION

A process of rapid impulse conduction that is conferred on axons by myelin sheaths in which the generation of an action potential leaps from one node (the exposed region of the axons between adjacent myelin sheaths) to the next.

ZINC FINGER

A protein module in which cysteine or cysteine–histidine residues coordinate a zinc ion. Zinc fingers are often used in DNA recognition and in protein–protein interactions.

PARACRINE SIGNALLING

This process involves cells secreting molecules that act on other cells in their immediate neighbourhood that express the appropriate receptors, rather than acting on the same cell (autocrine signalling) or on remote cells (endocrine signalling).

BASIC HELIX–LOOP–HELIX

A structural motif present in many transcription factors that is characterized by two α-helices separated by a loop. The helices mediate dimerization, and the adjacent basic region is required for DNA binding.

HOMEODOMAIN

A 60-amino-acid DNA-binding domain that comprises three α-helices.

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Franklin, R. Why does remyelination fail in multiple sclerosis?. Nat Rev Neurosci 3, 705–714 (2002). https://doi.org/10.1038/nrn917

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