Autophagy induction stabilizes microtubules and promotes axon regeneration after spinal cord injury
Autophagy induction stabilizes microtubules and promotes axon regeneration after spinal cord injury
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自噬诱导可稳定微管并促进脊髓损伤后轴突再生。
DOI：
10.1073/pnas.1611282113
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发表时间：
2016-10-04
影响因子：
11.1
通讯作者：
Luo, Zhen-Ge
中科院分区：
文献类型：
--
作者：
He, Miao;Ding, Yuetong;Luo, Zhen-Ge
细胞骨架结构的重塑，如微管组装，被认为是至关重要的生长锥启动和损伤轴突的再生。自噬在维持细胞内稳态中起重要作用，其功能障碍导致神经元变性。自噬在损伤后轴突再生中的作用仍然是推测性的。在这里，我们展示了自噬在调节微管动力学和轴突再生中的作用。我们发现，自噬诱导促进轴突生长，减弱非许可的底物髓鞘的抑制作用，并减少轴突损伤后的回缩球的形成在培养的皮层神经元。有趣的是，自噬诱导通过降解神经元中的微管分解蛋白SCG 10来稳定微管。在脊髓损伤的小鼠中，在损伤部位局部施用特异性自噬诱导肽Tat-beclin 1显著减弱了脊髓背柱轴突和皮质脊髓束的轴突回缩，并促进了长期观察后的下行轴突再生。最后，施用Tat-beclin 1改善了损伤小鼠的运动行为的恢复。这些结果显示了自噬诱导剂对受损轴突的有希望的作用，提供了支持自噬在轴突再生中的有益作用的直接证据。
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.