title: Autophagy Inhibition Favors Survival of Rubrospinal Neurons After Spinal Cord Hemisection.
abstract: Spinal cord injuries (SCIs) are devastating conditions of the central nervous system (CNS) for which there are no restorative therapies. Neuronal death at the primary lesion site and in remote regions that are functionally connected to it is one of the major contributors to neurological deficits following SCI.Disruption of autophagic flux induces neuronal death in many CNS injuries, but its mechanism and relationship with remote cell death after SCI are unknown. We examined the function and effects of the modulation of autophagy on the fate of axotomized rubrospinal neurons in a rat model of spinal cord dorsal hemisection (SCH) at the cervical level. Following SCH, we observed an accumulation of LC3-positive autophagosomes (APs) in the axotomized neurons 1 and 5 days after injury. Furthermore, this accumulation was not attributed to greater initiation of autophagy but was caused by a decrease in AP clearance, as demonstrated by the build-up of p62, a widely used marker of the induction of autophagy. In axotomized rubrospinal neurons, the disruption of autophagic flux correlated strongly with remote neuronal death and worse functional recovery. Inhibition of AP biogenesis by 3-methyladenine (3-MA) significantly attenuated remote degeneration and improved spontaneous functional recovery, consistent with the detrimental effects of autophagy in remote damage after SCH. Collectively, our results demonstrate that autophagic flux is blocked in axotomized neurons on SCI and that the inhibition of AP formation improves their survival. Thus, autophagy is a promising target for the development of therapeutic interventions in the treatment of SCIs.
authors: Santa Lucia Foundation, I.R.C.C.S, Via del Fosso di Fiorano 64, 00143, Rome, Italy.
authors: Elisa
authors: E
authors: Bisicchia
authors: Santa Lucia Foundation, I.R.C.C.S, Via del Fosso di Fiorano 64, 00143, Rome, Italy.
authors: Laura
authors: L
authors: Latini
authors: Santa Lucia Foundation, I.R.C.C.S, Via del Fosso di Fiorano 64, 00143, Rome, Italy.
authors: Virve
authors: V
authors: Cavallucci
authors: Santa Lucia Foundation, I.R.C.C.S, Via del Fosso di Fiorano 64, 00143, Rome, Italy.
authors: Valeria
authors: V
authors: Sasso
authors: Clinical Department of Medical, Surgical and Health Science, University of Trieste, Trieste, Italy.
authors: Vanessa
authors: V
authors: Nicolin
authors: Santa Lucia Foundation, I.R.C.C.S, Via del Fosso di Fiorano 64, 00143, Rome, Italy.
authors: Marco
authors: M
authors: Molinari
authors: Santa Lucia Foundation, I.R.C.C.S, Via del Fosso di Fiorano 64, 00143, Rome, Italy. m.damelio@unicampus.it.|Department of Medicine, Unit of Molecular Neurosciences, University Campus-Biomedico, Via Alvaro del Portillo, 21, I-00128, Rome, Italy. m.damelio@unicampus.it.
authors: Marcello
authors: M
authors: D'Amelio
authors: Santa Lucia Foundation, I.R.C.C.S, Via del Fosso di Fiorano 64, 00143, Rome, Italy. mt.viscomi@hsantalucia.it.
authors: Maria Teresa
authors: MT
authors: Viscomi
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D004195:Disease Models, Animal; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000473:pathology*
chemical_list: D008869:Microtubule-Associated Proteins; C025946:3-methyladenine; D000225:Adenine
keywords: Autophagosomes; Autophagy; Autophagy flux; Neurodegeneration; Remote damage; Spinal cord injury