He Miao, Ding Yuetong, Chu Chen, Tang Jing, Xiao Qi, Luo Zhen-Ge
Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Proc Natl Acad Sci U S A. 2016 Oct 4;113(40):11324-11329. doi: 10.1073/pnas.1611282113. Epub 2016 Sep 16.
Remodeling of cytoskeleton structures, such as microtubule assembly, is believed to be crucial for growth cone initiation and regrowth of injured axons. Autophagy plays important roles in maintaining cellular homoeostasis, and its dysfunction causes neuronal degeneration. The role of autophagy in axon regeneration after injury remains speculative. Here we demonstrate a role of autophagy in regulating microtubule dynamics and axon regeneration. We found that autophagy induction promoted neurite outgrowth, attenuated the inhibitory effects of nonpermissive substrate myelin, and decreased the formation of retraction bulbs following axonal injury in cultured cortical neurons. Interestingly, autophagy induction stabilized microtubules by degrading SCG10, a microtubule disassembly protein in neurons. In mice with spinal cord injury, local administration of a specific autophagy-inducing peptide, Tat-beclin1, to lesion sites markedly attenuated axonal retraction of spinal dorsal column axons and cortical spinal tract and promoted regeneration of descending axons following long-term observation. Finally, administration of Tat-beclin1 improved the recovery of motor behaviors of injured mice. These results show a promising effect of an autophagy-inducing reagent on injured axons, providing direct evidence supporting a beneficial role of autophagy in axon regeneration.
细胞骨架结构的重塑，如微管组装，被认为对生长锥的启动和受损轴突的再生至关重要。自噬在维持细胞内环境稳定中发挥重要作用，其功能障碍会导致神经元变性。自噬在损伤后轴突再生中的作用仍存在推测性。在此，我们证明了自噬在调节微管动力学和轴突再生中的作用。我们发现自噬诱导促进了神经突生长，减弱了非允许性底物髓磷脂的抑制作用，并减少了培养的皮质神经元轴突损伤后回缩球的形成。有趣的是，自噬诱导通过降解神经元中的微管拆卸蛋白SCG10来稳定微管。在脊髓损伤的小鼠中，向损伤部位局部施用特定的自噬诱导肽Tat-beclin1，经过长期观察，明显减弱了脊髓背柱轴突和皮质脊髓束的轴突回缩，并促进了下行轴突的再生。最后，施用Tat-beclin1改善了受伤小鼠运动行为的恢复。这些结果表明自噬诱导试剂对受损轴突有显著作用，为支持自噬在轴突再生中有益作用提供了直接证据。
