Fournier A E, GrandPre T, Strittmatter S M
Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Nature. 2001 Jan 18;409(6818):341-6. doi: 10.1038/35053072.
Nogo has been identified as a component of the central nervous system (CNS) myelin that prevents axonal regeneration in the adult vertebrate CNS. Analysis of Nogo-A has shown that an axon-inhibiting domain of 66 amino acids is expressed at the extracellular surface and at the endoplasmic reticulum lumen of transfected cells and oligodendrocytes. The acidic amino terminus of Nogo-A is detected at the cytosolic face of cellular membranes and may contribute to inhibition of axon regeneration at sites of oligodendrocyte injury. Here we show that the extracellular domain of Nogo (Nogo-66) inhibits axonal extension, but does not alter non-neuronal cell morphology. In contrast, a multivalent form of the N terminus of Nogo-A affects the morphology of both neurons and other cell types. Here we identify a brain-specific, leucine-rich-repeat protein with high affinity for soluble Nogo-66. Cleavage of the Nogo-66 receptor and other glycophosphatidylinositol-linked proteins from axonal surfaces renders neurons insensitive to Nogo-66. Nogo-66 receptor expression is sufficient to impart Nogo-66 axonal inhibition to unresponsive neurons. Disruption of the interaction between Nogo-66 and its receptor provides the potential for enhanced recovery after human CNS injury.
Nogo已被确定为中枢神经系统（CNS）髓磷脂的一个成分，它会阻止成年脊椎动物中枢神经系统中的轴突再生。对Nogo-A的分析表明，一个由66个氨基酸组成的轴突抑制结构域在转染细胞和少突胶质细胞的细胞外表面及内质网腔中表达。Nogo-A的酸性氨基末端在细胞膜的胞质面被检测到，可能在少突胶质细胞损伤部位对轴突再生的抑制中起作用。在这里我们表明，Nogo的细胞外结构域（Nogo-66）会抑制轴突延伸，但不会改变非神经元细胞的形态。相比之下，Nogo-A氨基末端的多价形式会影响神经元和其他细胞类型的形态。在这里我们鉴定出一种对可溶性Nogo-66具有高亲和力的脑特异性、富含亮氨酸重复序列的蛋白质。从轴突表面切割Nogo-66受体和其他糖基磷脂酰肌醇连接蛋白会使神经元对Nogo-66不敏感。Nogo-66受体的表达足以赋予无反应神经元对Nogo-66的轴突抑制作用。破坏Nogo-66与其受体之间的相互作用为人类中枢神经系统损伤后增强恢复提供了可能性。
