John Van Geest Centre for Brain Repair, University of Cambridge, Robinson Way, Cambridge, CB2 0PY, UK.
Centre of Reconstructive Neuroscience, Institute for Experimental Medicine ASCR, Prague, Czech Republic.
Neurochem Res. 2020 Jan;45(1):144-158. doi: 10.1007/s11064-019-02844-y. Epub 2019 Aug 6.
Axon regeneration in the CNS is inhibited by many extrinsic and intrinsic factors. Because these act in parallel, no single intervention has been sufficient to enable full regeneration of damaged axons in the adult mammalian CNS. In the external environment, NogoA and CSPGs are strongly inhibitory to the regeneration of adult axons. CNS neurons lose intrinsic regenerative ability as they mature: embryonic but not mature neurons can grow axons for long distances when transplanted into the adult CNS, and regeneration fails with maturity in in vitro axotomy models. The causes of this loss of regeneration include partitioning of neurons into axonal and dendritic fields with many growth-related molecules directed specifically to dendrites and excluded from axons, changes in axonal signalling due to changes in expression and localization of receptors and their ligands, changes in local translation of proteins in axons, and changes in cytoskeletal dynamics after injury. Also with neuronal maturation come epigenetic changes in neurons, with many of the transcription factor binding sites that drive axon growth-related genes becoming inaccessible. The overall aim for successful regeneration is to ensure that the right molecules are expressed after axotomy and to arrange for them to be transported to the right place in the neuron, including the damaged axon tip.
中枢神经系统中的轴突再生受到许多外在和内在因素的抑制。由于这些因素是平行作用的，因此没有单一的干预措施足以使成年哺乳动物中枢神经系统中受损的轴突完全再生。在外部环境中，NogoA 和 CSPGs 对成年轴突的再生具有强烈的抑制作用。中枢神经系统神经元在成熟过程中失去内在的再生能力：胚胎神经元而非成熟神经元在移植到成年中枢神经系统后可以远距离生长轴突，并且在体外轴突切断模型中随着成熟而导致再生失败。这种再生能力丧失的原因包括神经元分为轴突和树突区，许多与生长相关的分子专门定向树突，而被排除在轴突之外，由于受体及其配体的表达和定位的变化，轴突信号发生变化，轴突中蛋白质的局部翻译发生变化，以及损伤后细胞骨架动力学发生变化。随着神经元的成熟，神经元中也会发生表观遗传变化，驱动轴突生长相关基因的许多转录因子结合位点变得无法接近。成功再生的总体目标是确保在轴突切断后正确表达分子，并安排它们运输到神经元中的正确位置，包括受损的轴突末端。
