Limiting multiple sclerosis related axonopathy by blocking Nogo receptor and CRMP-2 phosphorylation
Limiting multiple sclerosis related axonopathy by blocking Nogo receptor and CRMP-2 phosphorylation
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DOI：
10.1093/brain/aws100
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发表时间：
2012-06-01
期刊：
影响因子：
14.5
通讯作者：
Bernard, Claude C. A.
中科院分区：
文献类型：
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作者：
Petratos, Steven;Ozturk, Ezgi;Bernard, Claude C. A.
多发性硬化包括脱髓鞘和中枢神经系统轴突变性。在多发性硬化症及其小鼠模型——实验性自身免疫性脑脊髓炎中，轴突变性的分子机制尚不清楚。我们之前报道过，针对轴突生长抑制剂Nogo-A，可以防止实验性自身免疫性脑脊髓炎的神经退行性变；然而，发生这种情况的机制尚不清楚。我们现在发现坍缩蛋白反应介质蛋白2 （CRMP-2）是一种重要的调节轴突生长的微管蛋白相关蛋白，在实验性自身免疫性脑脊髓炎变性轴突的进展过程中被磷酸化并因此受到抑制。CRMP-2的磷酸化形式（pThr555CRMP-2）定位于慢性活动性多发性硬化症病变的脊髓神经元和轴突。具体来说，pThr555CRMP-2与Nogo-66受体1（NgR1）依赖性有关，因为髓鞘少突胶质细胞糖蛋白（MOG）（35-55）诱导的NgR1敲除（NgR1(-/-)）小鼠表现出实验性自身免疫性脑脊髓炎疾病进展减少，而NgR1 (-/-) MOG（35-55）反应性淋巴细胞和单核细胞没有失调。实验性自身免疫性脑脊髓炎诱导的ngr1（-/-）小鼠轴突变性/丧失的局限性与实验性自身免疫性脑脊髓炎期间脊髓和视神经中pThr555CRMP-2水平降低有关。此外，用编码位点特异性突变体T555ACRMP-2构建体的腺相关病毒载体转导视网膜神经节细胞，限制了实验性自身免疫性脑脊髓炎高峰期视神经轴突变性的发生。在实验性自身免疫性脑脊髓炎过程中治疗性给予抗nogo（623-640）抗体，与改善临床结果相关，已被证明可消除脊髓中pThr555CRMP-2蛋白水平并改善病理结果。我们得出结论，CRMP-2的磷酸化可能在NgR1激活的下游，并在实验性自身免疫性脑脊髓炎和多发性硬化症的轴突变性中发挥作用。阻断Nogo-A/NgR1相互作用可能是多发性硬化症可行的治疗靶点。
Multiple sclerosis involves demyelination and axonal degeneration of the central nervous system. The molecular mechanisms of axonal degeneration are relatively unexplored in both multiple sclerosis and its mouse model, experimental autoimmune encephalomyelitis. We previously reported that targeting the axonal growth inhibitor, Nogo-A, may protect against neurodegeneration in experimental autoimmune encephalomyelitis; however, the mechanism by which this occurs is unclear. We now show that the collapsin response mediator protein 2 (CRMP-2), an important tubulin-associated protein that regulates axonal growth, is phosphorylated and hence inhibited during the progression of experimental autoimmune encephalomyelitis in degenerating axons. The phosphorylated form of CRMP-2 (pThr555CRMP-2) is localized to spinal cord neurons and axons in chronic-active multiple sclerosis lesions. Specifically, pThr555CRMP-2 is implicated to be Nogo-66 receptor 1 (NgR1)-dependent, since myelin oligodendrocyte glycoprotein (MOG)(35-55)-induced NgR1 knock-out (ngr1(-/-)) mice display a reduced experimental autoimmune encephalomyelitis disease progression, without a deregulation of ngr1(-/-) MOG(35-55)-reactive lymphocytes and monocytes. The limitation of axonal degeneration/loss in experimental autoimmune encephalomyelitis-induced ngr1(-/-) mice is associated with lower levels of pThr555CRMP-2 in the spinal cord and optic nerve during experimental autoimmune encephalomyelitis. Furthermore, transduction of retinal ganglion cells with an adeno-associated viral vector encoding a site-specific mutant T555ACRMP-2 construct, limits optic nerve axonal degeneration occurring at peak stage of experimental autoimmune encephalomyelitis. Therapeutic administration of the anti-Nogo(623-640) antibody during the course of experimental autoimmune encephalomyelitis, associated with an improved clinical outcome, is demonstrated to abrogate the protein levels of pThr555CRMP-2 in the spinal cord and improve pathological outcome. We conclude that phosphorylation of CRMP-2 may be downstream of NgR1 activation and play a role in axonal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis. Blockade of Nogo-A/NgR1 interaction may serve as a viable therapeutic target in multiple sclerosis.