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The Journal of Neuroscience, February 27, 2008, 28(9):2168-2178; doi:10.1523/JNEUROSCI.5232-07.2008

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Neurobiology of Disease
Eif-2a Protects Brainstem Motoneurons in a Murine Model of Sleep Apnea

Yan Zhu, Polina Fenik, Guanxia Zhan, Ben Sanfillipo-Cohn, Nirinjini Naidoo, and Sigrid C. Veasey

Center for Sleep and Neurobiology and Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Dr. Sigrid C. Veasey, University of Pennsylvania, Translational Research Building, Room 2115, 125 South 31st Street, Philadelphia, PA 19104. Email: veasey{at}mail.med.upenn.edu

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-2 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.

Key words: motor neuron; injury; hypoxia/reoxygenation; oxidative; hypoglossal; apoptosis

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Received Nov. 26, 2007; revised Jan. 10, 2008; accepted Jan. 11, 2008.

Correspondence should be addressed to Dr. Sigrid C. Veasey, University of Pennsylvania, Translational Research Building, Room 2115, 125 South 31st Street, Philadelphia, PA 19104. Email: veasey{at}mail.med.upenn.edu

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