ATG5 overexpression is neuroprotective and attenuates cytoskeletal and vesicle-trafficking alterations in axotomized motoneurons

• DOI: 10.1038/s41419-018-0682-y
• Publication Date: 2018-05-24T09:50:22Z
• Authors: Tatiana Leiva-Rod...; David Romeo-Guitart; Sara Marmolejo-Ma...; Mireia Herrando-G...; Assumpció Bosch; Joaquim Forés; Caty Casas
• Keywords: Axotomy

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