Autophagy induction stabilizes microtubules and promotes axon regeneration after spinal cord injury

Significance

Autophagy maintains cellular homoeostasis by bulk or selective degradation of cytoplasmic components including organelles or protein aggregates. Its role in axon regeneration remains speculative. Here, we found that boosting autophagy stabilized microtubules by degrading a microtubule destabilizing protein, SCG10 (superior cervical ganglia protein 10), in cultured CNS neurons and promoted axon growth. Furthermore, treatment with a specific autophagy-inducing peptide, Tat-beclin1, attenuated axon retraction, promoted axon regeneration, and improved locomotor functional recovery in mice with spinal cord injury. This study reveals a critical role of autophagy in stabilizing neuronal microtubules and a promising therapeutic effect of an autophagy-inducing reagent on CNS axons following injury.

Abstract

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.