Injured neurons should engage endogenous mechanisms of self-protection to limit neurodegeneration. Enhancing efficacy of these mechanisms or correcting dysfunctional pathways may be a successful strategy for inducing neuroprotection. Spinal motoneurons retrogradely degenerate after proximal axotomy due to mechanical detachment (avulsion) of the nerve roots, and this limits recovery of nervous system function in patients after this type of trauma. In a previously reported proteomic analysis, we demonstrated that autophagy is a key endogenous mechanism that may allow motoneuron survival and regeneration after distal axotomy and suture of the nerve. Herein, we show that autophagy flux is dysfunctional or blocked in degenerated motoneurons after root avulsion. We also found that there were abnormalities in anterograde/retrograde motor proteins, key secretory pathway factors, and lysosome function. Further, LAMP1 protein was missorted and underglycosylated as well as the proton pump v-ATPase. In vitro modeling revealed how sequential disruptions in these systems likely lead to neurodegeneration. In vivo, we observed that cytoskeletal alterations, induced by a single injection of nocodazole, were sufficient to promote neurodegeneration of avulsed motoneurons. Besides, only pre-treatment with rapamycin, but not post-treatment, neuroprotected after nerve root avulsion. In agreement, overexpressing ATG5 in injured motoneurons led to neuroprotection and attenuation of cytoskeletal and trafficking-related abnormalities. These discoveries serve as proof of concept for autophagy-target therapy to halting the progression of neurodegenerative processes.

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Postmitotic cells, like neurons, must live through a lifetime. For this reason, organisms/cells have evolved with self-repair mechanisms that allow them to have a long life. The discovery workflow of neuroprotectors during the last years has focused on blocking the pathophysiological mechanisms that lead to neuronal loss in neurodegeneration. Unfortunately, only a few strategies from these studies were able to slow down or prevent neurodegeneration. There is compelling evidence demonstrating that endorsing the self-healing mechanisms that organisms/cells endogenously have, commonly referred to as cellular resilience, can arm neurons and promote their self-healing. Although enhancing these mechanisms has not yet received sufficient attention, these pathways open up new therapeutic avenues to prevent neuronal death and ameliorate neurodegeneration. Here, we highlight the main endogenous mechanisms of protection and describe their role in promoting neuron survival during neurodegeneration.