Signals to promote myelin formation and repair

Abstract

The myelin sheath wraps large axons in both the CNS and the PNS, and is a key determinant of efficient axonal function and health. Myelin is targeted in a series of diseases, notably multiple sclerosis (MS). In MS, demyelination is associated with progressive axonal damage, which determines the level of patient disability. The few treatments that are available for combating myelin damage in MS and related disorders, which largely comprise anti-inflammatory drugs, only show limited efficacy in subsets of patients. More-effective treatment of myelin disorders will probably be accomplished by early intervention with combinatorial therapies that target inflammation and other processes—for example, signaling pathways that promote remyelination. Indeed, evidence suggests that such pathways might be impaired in pathology and, hence, contribute to the failure of remyelination in such diseases. In this article, we review the molecular basis of signaling pathways that regulate myelination in the CNS and PNS, with a focus on signals that affect differentiation of myelinating glia. We also discuss factors such as extracellular molecules that act as modulators of these pathways. Finally, we consider the few preclinical and clinical trials of agents that augment this signaling.

Key Points

  • Myelinating glia and their associated axons transmit reciprocal signals that are necessary for the development and maintenance of the myelin–axon unit

  • Both extracellular and intracellular components of myelin–axon signaling pathways are perturbed in myelin diseases, thereby causing axonal damage

  • The level of disability in patients with myelin disorders correlates more with the extent of axonal damage than with the degree of myelin alteration

  • Evidence suggests that insults to myelin or myelinating glia cause secondary axonal damage; thus, myelin or glia are logical targets for early therapeutic intervention

  • Preclinical trials of agents that promote myelination provide hope that combinatorial treatments that target both this process and inflammation can be developed for myelin-related diseases

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Figure 1: The myelin–axon unit.
Figure 2: Axon to glia signaling in myelination during CNS development.
Figure 3: Axon to glia signaling in myelination during PNS development.

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Acknowledgements

Work in the laboratories of C. Taveggia, M. L. Feltri and L. Wrabetz is supported by grants from Fondazione Italiana Sclerosi Multipla, Italy; Telethon, Italy; Compagnia di San Paolo, Italy; Fondazione Mariani, Italy; the NIH, USA; and the European Union. We apologize to colleagues whose relevant work we were unable to cite because of space limitations.

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Taveggia, C., Feltri, M. & Wrabetz, L. Signals to promote myelin formation and repair. Nat Rev Neurol 6, 276–287 (2010). https://doi.org/10.1038/nrneurol.2010.37

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