Year: 2016
Type: article
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.
Source: Autophagy
Institutions: University of Gothenburg, University of Lausanne, Zhengzhou Children's Hospital, Third Affiliated Hospital of Zhengzhou University, Juntendo University, Zhengzhou University, Centre Hospitalier Universitaire Vaudois, Inserm, Institut Gustave Roussy, Sorbonne Paris Cité, Centre de Recherche des Cordeliers, La Ligue Contre le Cancer, Université Paris Descartes, Université Pierre-et-Marie-Curie, Karolinska University Hospital, Karolinska Institutet
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $768
Funders: National Science Foundation, Swedish Cancer Foundation, Fondation Leducq, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, National Natural Science Foundation of China, Stiftelserna Wilhelm och Martina Lundgrens, Vetenskapsrådet, Göteborgs Läkaresällskap, Barncancerfonden, Université de Lausanne, Svenska Läkaresällskapet, Japan Society for the Promotion of Science
Awards: Immunohistochemical evaluation of mitochondrial quality control in vivo, Defining how autophagy inhibition mediates neuroprotection in neonatal cerebral hypoxia-ischemia, G3146149251, G7031156480, Autophagy as a key mediator of delayed neuronal death in excitotoxicity and neonatal cerebral hypoxia-ischemia, G8690818240
OpenAlex ID: W2232187600