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.
Exp Neurol. 2010 Sep;225(1):18-23. doi: 10.1016/j.expneurol.2009.12.020. Epub 2010 Jan 4.
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.
保护轴突免受退化是髓鞘疾病治疗中的一个主要未满足的需求，特别是多发性硬化症（MS）目前无法治疗的继发性进展阶段。有几条证据表明，确保髓鞘鞘被修复到脱髓鞘的轴突上，即髓鞘再生的再生过程，是实现轴突保护的最有效手段之一。髓鞘再生可以作为脱髓鞘后的一种高度有效的自发再生过程发生。然而，由于尚未完全理解的原因，这一过程在 MS 中常常是不完全的或失败的。认识到髓鞘再生失败的原因，从而确定治疗靶点，将取决于对髓鞘疾病的详细组织病理学研究和对调节髓鞘再生的分子机制的详细了解。病理学研究表明，MS 中慢性脱髓鞘病变经常不能修复，是由于负责髓鞘再生的前体细胞分化失败，而不是它们的募集失败。在本文中，我们综述了调节前体细胞分化为髓鞘形成少突胶质细胞的三种机制——Notch 通路、Wnt 通路和髓鞘碎片中分化抑制剂激活的通路，并指出如何通过药理学手段靶向这些机制来克服髓鞘再生失败。
