title: Disrupted autophagy after spinal cord injury is associated with ER stress and neuronal cell death.
abstract: Autophagy is a catabolic mechanism facilitating degradation of cytoplasmic proteins and organelles in a lysosome-dependent manner. Autophagy flux is necessary for normal neuronal homeostasis and its dysfunction contributes to neuronal cell death in several neurodegenerative diseases. Elevated autophagy has been reported after spinal cord injury (SCI); however, its mechanism, cell type specificity and relationship to cell death are unknown. Using a rat model of contusive SCI, we observed accumulation of LC3-II-positive autophagosomes starting at posttrauma day 1. This was accompanied by a pronounced accumulation of autophagy substrate protein p62, indicating that early elevation of autophagy markers reflected disrupted autophagosome degradation. Levels of lysosomal protease cathepsin D and numbers of cathepsin-D-positive lysosomes were also decreased at this time, suggesting that lysosomal damage may contribute to the observed defect in autophagy flux. Normalization of p62 levels started by day 7 after SCI, and was associated with increased cathepsin D levels. At day 1 after SCI, accumulation of autophagosomes was pronounced in ventral horn motor neurons and dorsal column oligodendrocytes and microglia. In motor neurons, disruption of autophagy strongly correlated with evidence of endoplasmic reticulum (ER) stress. As autophagy is thought to protect against ER stress, its disruption after SCI could contribute to ER-stress-induced neuronal apoptosis. Consistently, motor neurons showing disrupted autophagy co-expressed ER-stress-associated initiator caspase 12 and cleaved executioner caspase 3. Together, these findings indicate that SCI causes lysosomal dysfunction that contributes to autophagy disruption and associated ER-stress-induced neuronal apoptosis.
authors.affiliation: Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Sarkar
authors.affiliation: Department of Anesthesiology, Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Dinizo
authors.affiliation: 1] Department of Anesthesiology, Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, USA [2] Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: A I
authors.initials: AI
authors.lastname: Faden
authors.affiliation: Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: E Y
authors.initials: EY
authors.lastname: Koh
authors.affiliation: 1] Department of Anesthesiology, Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, USA [2] Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Lipinski
authors.affiliation: Department of Anesthesiology, Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D059865:Endoplasmic Reticulum Stress; D066128:Gray Matter / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000378:metabolism; D009474:Neurons / Q000473:pathology*; D009836:Oligodendroglia / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000473:pathology*; D066127:White Matter / Q000473:pathology