Nogo-66 receptor antagonist peptide promotes axonal regeneration
Nogo-66 receptor antagonist peptide promotes axonal regeneration
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DOI：
10.1038/417547a
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发表时间：
2002-05-30
期刊：
影响因子：
64.8
通讯作者：
Strittmatter, SM
中科院分区：
文献类型：
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作者：
GrandPré, T;Li, SX;Strittmatter, SM
髓鞘来源的轴突生长抑制物，如Nogo，可能是成年哺乳动物创伤后中枢神经系统(CNS)缺乏轴突再生的原因。Nogo的66个残基结构域(Nogo-66)表达在少突胶质细胞表面(1)，并通过轴突Nogo-66受体(2)抑制轴突生长。IN-1单抗识别Nogo-A并促进皮质脊髓束再生和运动恢复(3-5)；然而，Nogo中IN-1表位的未知性、IN-1对Nogo的有限特异性以及非特异性的抗髓鞘效应使人们对Nogo-66或NGR的作用难以得出确切的结论。在这里，我们从Nogo-66的氨基末端多肽片段中鉴定出NgR的竞争性拮抗剂。Nogo-66(1-40)拮抗肽(Np1-40)在体外阻断Nogo-66或CNS髓鞘对轴突生长的抑制作用，表明NgR介导了髓鞘抑制轴突生长的很大部分。脊髓半横断大鼠鞘内注射NEP1-40可显著促进皮质脊髓束轴突生长，促进功能恢复。因此，Nogo-66和NGR在限制中枢神经系统损伤后轴突再生中起着中心作用，而Np1-40提供了一种潜在的治疗药物。
Myelin-derived axon outgrowth inhibitors, such as Nogo, may account for the lack of axonal regeneration in the central nervous system (CNS) after trauma in adult mammals. A 66-residue domain of Nogo (Nogo-66) is expressed on the surface of oligodendrocytes(1) and can inhibit axonal outgrowth through an axonal Nogo-66 receptor (NgR)(2). The IN-1 monoclonal antibody recognizes Nogo-A and promotes corticospinal tract regeneration and locomotor recovery(3-5); however, the undefined nature of the IN-1 epitope in Nogo, the limited specificity of IN-1 for Nogo, and nonspecific anti-myelin effects have prevented a firm conclusion about the role of Nogo-66 or NgR. Here, we identify competitive antagonists of NgR derived from amino-terminal peptide fragments of Nogo-66. The Nogo-66(1-40) antagonist peptide (NEP1-40) blocks Nogo-66 or CNS myelin inhibition of axonal outgrowth in vitro, demonstrating that NgR mediates a significant portion of axonal outgrowth inhibition by myelin. Intrathecal administration of NEP1-40 to rats with mid-thoracic spinal cord hemisection results in significant axon growth of the corticospinal tract, and improves functional recovery. Thus, Nogo-66 and NgR have central roles in limiting axonal regeneration after CNS injury, and NEP1-40 provides a potential therapeutic agent.