Multiple Sclerosis, Devastating Demyelinating Disease

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Introduction Multiple sclerosis (MS) is a devastating demyelinating disease affecting the central nervous system (CNS) and resulting in impaired motor and sensory function (Karussis, 2014, p. 134). MS is characterized by three main features: inflammation, and the resulting demyelination and axonal damage (Karussis, 2014, p. 134). An inflammatory response is initiated when T cells attack myelin, recognizing self-antigens as foreign (Karussis, 2014, p. 134). The inflammatory response propagates demyelination and axonal damage (Karussis, 2014, p. 135). A major cell involved in the pathogenesis of MS, oligodendrocytes (OLs) are responsible for creating myelin (Zhang et al., 2009, p. 19162). MS patients present with reduced numbers of OLs, resulting in less production of myelin and impaired speed of neural transmission (Karussis, 2014, p. 134). In initial stages of the disease, remyelination occurs; however, as MS progresses, OLs become less able to repair the damage (Zhang et al., 2009, p. 19162). Notch1 and its ligand, Jagged1, have been identified as critical mediators of oligodendrocyte progenitor cell (OPC) recruitment and differentiation (Zhang et al., 2009, p. 19162). OPCs are recruited to demyelinated axons, where they differentiate into OLs, producing myelin to remyelinate CNS axons (Jurynczyk & Selmaj, 2010, p. 7). Notch1 receptors are found on OPCs and Jagged1 ligands are present on adjacent axons and glial cells (Woodhoo et al., 2009, p. 841). MS lesions have characteristically high numbers of Notch1 receptors; additionally, Jagged1 is also abundant in MS lesions (Stidworthy et al., 2004, pp. 1931-1934). Interactions between Notch1 and Jagged1 result in the failure of OPCs to differentiate into OLs, in turn impairing OPC... ... middle of paper ... ... p. 134). The Notch1/Jagged1 pathway is extensively involved in demyelination and, as such, is a therapeutic target for remyelination of CNS axons in individuals with MS (Zhang et al., 2009, p. 19162). Through a cascade of intracellular events, the binding of Jagged1 to Notch1 induces the suppression of transcription factors that prevent the differentiation of neural precursor cells to OPCs (Aparicio et al., 2013, p. 820). Consequently, the OPCs cannot undergo further maturation into OLs, resulting in impaired ability to repair demyelinated axons (Aparicio et al., 2013, p. 829). The Notch1/Jagged1 pathway is ideal as a therapeutic target for remyelination, as there are several steps that can be interfered with (Zhang et al., 2009, p. 19162). Impairment of the Notch1/Jagged1 pathway allows for OL maturation and the resulting remyelination (Perez et al., 2013, p. 273).

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