title: Neuroprotection by selective neuronal deletion of Atg7 in neonatal brain injury.
abstract: Perinatal asphyxia induces neuronal cell death and brain injury, and is often associated with irreversible neurological deficits in children. There is an urgent need to elucidate the neuronal death mechanisms occurring after neonatal hypoxia-ischemia (HI). We here investigated the selective neuronal deletion of the Atg7 (autophagy related 7) gene on neuronal cell death and brain injury in a mouse model of severe neonatal hypoxia-ischemia. Neuronal deletion of Atg7 prevented HI-induced autophagy, resulted in 42% decrease of tissue loss compared to wild-type mice after the insult, and reduced cell death in multiple brain regions, including apoptosis, as shown by decreased caspase-dependent and -independent cell death. Moreover, we investigated the lentiform nucleus of human newborns who died after severe perinatal asphyxia and found increased neuronal autophagy after severe hypoxic-ischemic encephalopathy compared to control uninjured brains, as indicated by the numbers of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3)-, LAMP1 (lysosomal-associated membrane protein 1)-, and CTSD (cathepsin D)-positive cells. These findings reveal that selective neuronal deletion of Atg7 is strongly protective against neuronal death and overall brain injury occurring after HI and suggest that inhibition of HI-enhanced autophagy should be considered as a potential therapeutic target for the treatment of human newborns developing severe hypoxic-ischemic encephalopathy.
authors.affiliation: a Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden.
authors.forename: Cuicui
authors.initials: C
authors.lastname: Xie
authors.affiliation: b Department of Fundamental Neurosciences , University of Lausanne , Lausanne , Switzerland.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Ginet
authors.affiliation: a Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden.|c Department of Pediatrics , Third Affiliated Hospital of Zhengzhou University , Zhengzhou , China.|d Department of Pediatrics , Zhengzhou Children's Hospital , Zhengzhou , China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: e Department of Cellular and Molecular Neuropathology , Juntendo University School of Medicine , Tokyo , Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Koike
authors.affiliation: a Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhou
authors.affiliation: a Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden.|c Department of Pediatrics , Third Affiliated Hospital of Zhengzhou University , Zhengzhou , China.|d Department of Pediatrics , Zhengzhou Children's Hospital , Zhengzhou , China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: a Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden.|c Department of Pediatrics , Third Affiliated Hospital of Zhengzhou University , Zhengzhou , China.
authors.forename: Hongfu
authors.initials: H
authors.lastname: Li
authors.affiliation: a Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden.|c Department of Pediatrics , Third Affiliated Hospital of Zhengzhou University , Zhengzhou , China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: c Department of Pediatrics , Third Affiliated Hospital of Zhengzhou University , Zhengzhou , China.|f Perinatal Center, Sahlgrenska Academy; University of Gothenburg , Gothenburg , Sweden.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Wang
authors.affiliation: e Department of Cellular and Molecular Neuropathology , Juntendo University School of Medicine , Tokyo , Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
authors.affiliation: g Clinic of Neonatology; Department of Pediatrics and Pediatric Surgery, University Hospital Center , Lausanne , Switzerland.
authors.forename: Anita C
authors.initials: AC
authors.lastname: Truttmann
authors.affiliation: h INSERM U848, Institute Gustave Roussy , Villejuif , France.|i Université Paris Descartes/Paris V, Sorbonne Paris Cité , Paris , France.|j Université Pierre et Marie Curie , Paris , France.|k Equipe 11 labellisée Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers , Paris , France.|l Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus , Villejuif , France.|m Pôle de Biologie, Hôpital Européen Georges Pompidou , AP-HP, Paris , France.|n Department of Women's and Children's Health , Karolinska Institutet, Karolinska University Hospital , Stockholm , Sweden.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: b Department of Fundamental Neurosciences , University of Lausanne , Lausanne , Switzerland.|g Clinic of Neonatology; Department of Pediatrics and Pediatric Surgery, University Hospital Center , Lausanne , Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Puyal
authors.affiliation: n Department of Women's and Children's Health , Karolinska Institutet, Karolinska University Hospital , Stockholm , Sweden.
authors.forename: Klas
authors.initials: K
authors.lastname: Blomgren
authors.affiliation: a Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden.|c Department of Pediatrics , Third Affiliated Hospital of Zhengzhou University , Zhengzhou , China.
authors.forename: Changlian
authors.initials: C
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001238:Asphyxia Neonatorum / Q000473:pathology; D000071193:Autophagy-Related Protein 7 / Q000172:deficiency* / Q000378:metabolism; D001930:Brain Injuries / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003342:Corpus Striatum / Q000473:pathology; D004789:Enzyme Activation; D017353:Gene Deletion; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000150:complications / Q000473:pathology; D007231:Infant, Newborn; D007249:Inflammation / Q000150:complications / Q000378:metabolism / Q000473:pathology; D019426:Integrases / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D000066829:Neuroprotection; D021381:Protein Transport
chemical_list: D051033:Apoptosis Inducing Factor; C502661:Atg7 protein, mouse; D006360:Heat-Shock Proteins; C045073:Cre recombinase; D019426:Integrases; D053148:Caspase 3; D000071193:Autophagy-Related Protein 7
keywords: ATG7; apoptosis; autophagy; caspase; hypoxic-ischemic encephalopathy; newborn