title: Eif-2a protects brainstem motoneurons in a murine model of sleep apnea.
abstract: Obstructive sleep apnea is associated with neural injury and dysfunction. Hypoxia/reoxygenation exposures, modeling sleep apnea, injure select populations of neurons, including hypoglossal motoneurons. The mechanisms underlying this motoneuron injury are not understood. We hypothesize that endoplasmic reticulum injury contributes to motoneuron demise. Hypoxia/reoxygenation exposures across 8 weeks in adult mice upregulated the unfolded protein response as evidenced by increased phosphorylation of PERK [PKR-like endoplasmic reticulum (ER) kinase] in facial and hypoglossal motoneurons and persistent upregulation of CCAAT/enhancer-binding protein-homologous protein (CHOP)/growth arrest and DNA damage-inducible protein (GADD153) with nuclear translocation. Long-term hypoxia/reoxygenation also resulted in cleavage and nuclear translocation of caspase-7 and caspase-3 in hypoglossal and facial motoneurons. In contrast, occulomotor and trigeminal motoneurons showed persistent phosphorylation of eIF-2a across hypoxia/reoxygenation, without activations of CHOP/GADD153 or either caspase. Ultrastructural analysis of rough ER in hypoglossal motoneurons revealed hypoxia/reoxygenation-induced luminal swelling and ribosomal detachment. Protection of eIF-2alpha phosphorylation with systemically administered salubrinal throughout hypoxia/reoxygenation exposure prevented CHOP/GADD153 activation in susceptible motoneurons. Collectively, this work provides evidence that long-term exposure to hypoxia/reoxygenation events, modeling sleep apnea, results in significant endoplasmic reticulum injury in select upper airway motoneurons. Augmentation of eIF-2a phosphorylation minimizes motoneuronal injury in this model. It is anticipated that obstructive sleep apnea results in endoplasmic reticulum injury involving motoneurons, whereas a critical balance of phosphorylated eIF-2a should minimize motoneuronal injury in obstructive sleep apnea.
authors.affiliation: Center for Sleep and Neurobiology and Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Polina
authors.initials: P
authors.lastname: Fenik
authors.forename: Guanxia
authors.initials: G
authors.lastname: Zhan
authors.forename: Ben
authors.initials: B
authors.lastname: Sanfillipo-Cohn
authors.forename: Nirinjini
authors.initials: N
authors.lastname: Naidoo
authors.forename: Sigrid C
authors.initials: SC
authors.lastname: Veasey
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002934:Cinnamates / Q000494:pharmacology; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000150:complications; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009046:Motor Neurons / Q000378:metabolism* / Q000648:ultrastructure; D018384:Oxidative Stress; D010766:Phosphorylation / Q000187:drug effects; D012891:Sleep Apnea Syndromes / Q000209:etiology / Q000473:pathology*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D020169:Caspases; D002795:Choline O-Acetyltransferase; D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; D013890:Thiourea; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C497250:Ddit3 protein, mouse; C496827:salubrinal