Inhibition of Notch signaling enhances tissue repair in an animal model of multiple sclerosis
Inhibition of Notch signaling enhances tissue repair in an animal model of multiple sclerosis
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DOI：
10.1016/j.jneuroim.2005.10.013
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发表时间：
2005-12-30
影响因子：
3.3
通讯作者：
Selmaj, K
中科院分区：
文献类型：
--
作者：
Jurynczyk, M;Jurewicz, A;Selmaj, K
在多发性硬化症（MS）中，少突胶质细胞（OL）不能再生被免疫攻击破坏的髓鞘，并且病变区域最终主要被星形胶质细胞瘢痕组织占据。MS中OL的丢失并不能解释有限的髓鞘修复，因为病变含有大量OL前体细胞（OPC）。Notch通路的激活已显示为OPC提供抑制信号并阻碍它们在CNS发育期间产生髓鞘的能力。在这里，我们表明，γ-分泌酶抑制Notch信号在OL的中枢神经系统的SJL/J小鼠与实验性自身免疫性脑脊髓炎（EAE）显着增强临床恢复和中枢神经系统，促进髓鞘再生和减少轴突损伤。功能测定证实了在经紫杉醇处理的组中Notch信号传导减少。因此，γ-分泌酶抑制导致更有利于髓鞘修复和轴突存活的环境。我们的研究结果表明，操纵成熟CNS中与Notch激活相关的环境提供了一个有希望的治疗靶点。（C）2005 Elsevier B. V.保留所有权利。
Oligodendrocytes (OLs) fail to regenerate myelin destroyed by the immune attack in multiple sclerosis (MS) and lesion areas are eventually largely occupied by astrocytic scar tissue. Loss of OLs in MS does not account for the limited myelin repair as lesions contain a considerable number of OL precursor cells (OPC). Activation of the Notch pathway has been shown to provide inhibitory signals for OPC and to hamper their ability to produce myelin during CNS development. Here we show that gamma-secretase inhibition of Notch signaling within OL of CNS of SJL/J mice with experimental autoimmune encephalomyelitis (EAE) significantly enhanced clinical recovery and in the CNS, promoted remyelination and reduced axonal damage. Functional assays confirmed decreased Notch signaling in inhibitor-treated groups. Therefore, gamma-secretase inhibition led to an environment more conducive to myelin repair and axonal survival. Our results suggest that manipulation of the environment associated with Notch activation in the mature CNS provides a promising therapeutic target in MS. (C) 2005 Elsevier B.V. All rights reserved.