Overcoming remyelination failure in multiple sclerosis and other myelin disorders.
Protecting axons from degeneration represents a major unmet need in the treatment of myelin disorders and especially the currently untreatable secondary progressive stages of multiple sclerosis (MS). Several lines of evidence indicate that ensuring myelin sheaths are restored to demyelinated axons, the regenerative process of remyelination, represents one of the most effective means of achieving axonal protection. Remyelination can occur as a highly effective spontaneous regenerative process following demyelination. However, for reasons that have not been fully understood, this process is often incomplete or fails in MS. Recognizing the reasons for remyelination failure and hence identifying therapeutic targets will depend on detailed histopathological studies of myelin disorders and a detailed understanding of the molecular mechanisms regulating remyelination. Pathology studies have revealed that chronically demyelinated lesions in MS often fail to repair because of a failure of differentiation of the precursor cell responsible for remyelination rather than a failure of their recruitment. In this article we review three mechanisms by which differentiation of precursor cells into remyelinating oligodendrocytes are regulated-the Notch pathway, the Wnt pathway and the pathways activated by inhibitor of differentiation in myelin debris-and indicate how these might be pharmacologically targeted to overcome remyelination failure.
Fancy
Stephen P J
SP
Department of Pediatrics, Eli and Edyth Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
Kotter
Mark R
MR
Harrington
Emily P
EP
Huang
Jeffrey K
JK
Zhao
Chao
C
Rowitch
David H
DH
Franklin
Robin J M
RJ
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D006801:Humans; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D009413:Nerve Fibers, Myelinated / Q000378:metabolism* / Q000473:pathology*; D009416:Nerve Regeneration / Q000187:drug effects* / Q000502:physiology*; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology