睡眠窒息（Sleep apnea）是一种睡眠时暂时性的呼吸中断，一晚上中断次数可达十几次甚至上百次。世界上无数的人深受其害。美国科学家近日为睡眠窒息患者带来了福音，他们首次发现了睡眠窒息的详细分子路径，有望据此开发出有效的治疗方案。相关论文发表在《神经学杂志》（Journal of Neuroscience）上。
领导此次研究的是美国宾夕法尼亚大学医学院的Sigrid C. Veasey。他说：“睡眠窒息时，细胞内的氧气水平降得太低，从而会释放觉醒信号，喘息着获取空气。这种情况会整夜整夜地发生，使得患者的睡眠质量急剧下降。”
在一个睡眠窒息的小鼠模型中，研究人员发现颚和面部运动神经元的内质网肿大，而内质网负责蛋白质的折叠工作。研究人员推测，这使得蛋白无法得到合适的折叠，随着细胞内氧气水平的下降和波动，错误折叠的蛋白就会积聚起来。Veasey表示，这是首次在细胞水平上发现内质网与睡眠窒息有关。
进一步的研究发现，内质网表面的感受蛋白能被内部的错误折叠蛋白激活。研究人员此次关注的是一个名为PERK的蛋白，当PERK蛋白被激活后，有两种情况可能会发生——细胞要么采取路径修补自己，要么毁灭自己。具体采取哪一种路径，取决于细胞原初的健康状况。
如果睡眠窒息患者拥有健康的细胞，细胞就会采取修补的路径。它们会激活另一种名为eIF-2alpha的分子，这种分子会激活抗氧化剂等有用分子来降解错误折叠的蛋白。
然而，如果细胞本来就是不健康的，PERK路径同样能够激活一些分子，使得细胞开启凋亡和死亡路径。Veasey说：“在这种情况下，患者有可能损失运动神经元，最终会恶化睡眠窒息症状，因为仅存的神经元在睡眠喘息时已经受到了很大的压迫。”
一种名为salubrinal的药物能够使eIF-2alpha保持活性，从而预防细胞走向死亡路径。但是salubrinal是一把双刃剑——适量能保持细胞健康，过量就会关闭所有的蛋白质合成，而这会产生很高的毒性。
研究小组目前正在改变小鼠的饮食以期提高eIF-2alpha路径的活性。Veasey说：“这项研究显示了哪种路径对于睡眠窒息的治疗是重要的。在salubrinal之外，我们需要找到新的治疗方案。如果最终我们能够找到保护内质网的方法，睡眠窒息也许就能得到缓解。”（科学网 梅进/编译）
生物谷推荐原始出处：
（Journal of Neuroscience），28(9):2168-2178，Yan Zhu，Sigrid C. Veasey
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@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.
