Regeneration after injury occurs in axons that lie in the peripheral nervous system but fails in the central nervous system, thereby limiting functional recovery. Differences in axonal signalling in response to injury that might underpin this differential regenerative ability are poorly characterized. Combining axoplasmic proteomics from peripheral sciatic or central projecting dorsal root ganglion (DRG) axons with cell body RNA-seq, we uncover injury-dependent signalling pathways that are uniquely represented in peripheral versus central projecting sciatic DRG axons. We identify AMPK as a crucial regulator of axonal regenerative signalling that is specifically downregulated in injured peripheral, but not central, axons. We find that AMPK in DRG interacts with the 26S proteasome and its CaMKIIα-dependent regulatory subunit PSMC5 to promote AMPKα proteasomal degradation following sciatic axotomy. Conditional deletion of AMPKα1 promotes multiple regenerative signalling pathways after central axonal injury and stimulates robust axonal growth across the spinal cord injury site, suggesting inhibition of AMPK as a therapeutic strategy to enhance regeneration following spinal cord injury.

损伤后的再生发生在位于周围神经系统中但在中枢神经系统中失败的轴突中，从而限制了功能恢复。轴突信号转导的差异可能是这种差异性再生能力的基础，但这种差异很难得到很好的表征。结合周围坐骨神经或中央突出的背根神经节（DRG）轴突与细胞体RNA-seq的轴质蛋白质组学，我们发现损伤依赖的信号转导途径，在外周与中央突出的坐骨神经DRG轴突中唯一代表。我们确定AMPK是轴突再生信号的关键调节剂，在受损的外周轴突而不是中枢轴突中特异性下调。我们发现DRG中的AMPK与26S蛋白酶体及其依赖CaMKIIα的调节亚基PSMC5相互作用，以促进坐骨神经切断后的AMPKα蛋白酶体降解。AMPKα1的条件性缺失可促进中枢轴突损伤后的多个再生信号通路，并刺激整个脊髓损伤部位的轴突生长旺盛，提示抑制AMPK是治疗脊髓损伤后增强再生的一种治疗策略。