Myelin failure in multiple sclerosis: Breaking the spell of Notch

Abstract

Loss of myelin, the fatty sheath that envelops most axons, is a hallmark of multiple sclerosis (MS). MS lesions can occur anywhere in the central nervous system (CNS). In most cases, demyelination is mediated by inflammatory cells and their secreted products, but the detailed mechanisms of myelin damage differ in the various types of MS (ref. 1). Axonal loss also occurs in MS, probably as a consequence of demyelination. Apart from oligodendrocytes, which produce the myelin sheath, MS lesions comprise axons and cells that provide neuronal support and protection, that is, astrocytes and microglia. In addition, inflammatory cells contribute to lesion formation by invading the CNS via small blood vessels. There they attack myelin, oligodendrocytes and perhaps axons as well (Fig. 1). In chronic lesions, the lost axons and myelin are replaced by dense, ‘sclerotic’ astrocytic scar tissue, hence the name multiple sclerosis. Spontaneous remyelination does occur in MS lesions, but in the long term it cannot prevent irreversible axonal damage. A study in this issue proposes a new link between the inflammatory milieu and the failure of efficient remyelination. John et al. suggest that inflammatory cells not only directly damage myelin, but they also create an environment in which surviving oligodendrocyte precursors fail to differentiate and myelinate. The authors report that transforming growth factorβ1 (TGF-β1), a cytokine produced by immune as well as other types of cells, stimulates astrocytes to express a surface protein called Jagged1. This protein binds to Notch receptors on the oligodendrocytes, and the receptors mediate signals that, in effect, inhibit the maturation of the oligodendrocytes. This pathway could provide a molecular handle for the therapeutic induction of myelination. In an elegant series of experiments, the investigators first identified candidate genes that are upregulated in cultured astrocytes after stimulation by the inflammatory cytokines present in

DOI: 10.1038/nm1002-1075
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@article{Hohlfeld2002MyelinFI, title={Myelin failure in multiple sclerosis: Breaking the spell of Notch}, author={R. Hohlfeld}, journal={Nature Medicine}, year={2002}, volume={8}, pages={1075-1076} }