Cellular Neuroscience, Neurodegeneration and Repair Program, Interdepartmental Neuroscience Program, Departments of Neurology and Neuroscience, Yale University School of Medicine, New Haven, CT 06536, USA.
Sci Signal. 2018 Apr 3;11(524):eaao4180. doi: 10.1126/scisignal.aao4180.
Axonal growth after traumatic spinal cord injury is limited by endogenous inhibitors, selective blockade of which promotes partial neurological recovery. The partial repair phenotypes suggest that compensatory pathways limit improvement. Gene expression profiles of mice deficient in , which encodes a receptor for myelin-associated inhibitors of axonal regeneration such as Nogo, revealed that trauma increased the mRNA expression of , which encodes the receptor for the opioid-related peptide nociceptin. Endogenous and overexpressed ORL1 coimmunoprecipitated with immature NgR1 protein, and ORL1 enhanced the O-linked glycosylation and surface expression of NgR1 in HEK293T and Neuro2A cells and primary neurons. ORL1 overexpression inhibited cortical neuron axon regeneration independently of NgR1. Furthermore, regeneration was inhibited by an ORL1 agonist and enhanced by the ORL1 antagonist J113397 through a ROCK-dependent mechanism. Mice treated with J113397 after dorsal hemisection of the mid-thoracic spinal cord recovered greater locomotor function and exhibited lumbar raphespinal axon sprouting. These effects were further enhanced by combined deletion and ORL1 inhibition. Thus, ORL1 limits neural repair directly and indirectly by enhancing NgR1 maturation, and ORL1 antagonists enhance recovery from traumatic CNS injuries in wild-type and null mice.
创伤性脊髓损伤后的轴突生长受到内源性抑制剂的限制，选择性阻断这些抑制剂可促进部分神经恢复。部分修复表型表明补偿途径限制了改善。缺乏编码髓鞘相关轴突再生抑制剂（如 Nogo 受体）的 基因的小鼠的基因表达谱显示，创伤增加了编码阿片样肽 nociceptin 受体的 基因的 mRNA 表达。内源性和过表达的 ORL1 与未成熟的 NgR1 蛋白共免疫沉淀，并且 ORL1 在 HEK293T 和 Neuro2A 细胞和原代神经元中增强 NgR1 的 O-连接糖基化和表面表达。ORL1 的过表达独立于 NgR1 抑制皮质神经元轴突再生。此外，ORL1 激动剂通过 ROCK 依赖性机制抑制再生，而 ORL1 拮抗剂 J113397 增强再生。在中胸段脊髓背侧半横切后用 J113397 处理的小鼠恢复了更好的运动功能，并表现出腰髓中缝脊髓轴突发芽。通过联合 缺失和 ORL1 抑制进一步增强了这些作用。因此，ORL1 通过增强 NgR1 成熟直接和间接限制神经修复，而 ORL1 拮抗剂增强野生型和 缺失小鼠创伤性中枢神经系统损伤的恢复。
