睡眠窒息（Sleep apnea）是一種睡眠時暫時性的呼吸中斷,，一晚上中斷次數(shù)可達十幾次甚至上百次,。世界上無數(shù)的人深受其害。美國科學(xué)家近日為睡眠窒息患者帶來了福音,，他們首次發(fā)現(xiàn)了睡眠窒息的詳細分子路徑,，有望據(jù)此開發(fā)出有效的治療方案。相關(guān)論文發(fā)表在《神經(jīng)學(xué)雜志》（Journal of Neuroscience）上,。
領(lǐng)導(dǎo)此次研究的是美國賓夕法尼亞大學(xué)醫(yī)學(xué)院的Sigrid C. Veasey,。他說：“睡眠窒息時，細胞內(nèi)的氧氣水平降得太低,，從而會釋放覺醒信號,，喘息著獲取空氣。這種情況會整夜整夜地發(fā)生,，使得患者的睡眠質(zhì)量急劇下降,。”
在一個睡眠窒息的小鼠模型中，研究人員發(fā)現(xiàn)顎和面部運動神經(jīng)元的內(nèi)質(zhì)網(wǎng)腫大,，而內(nèi)質(zhì)網(wǎng)負責(zé)蛋白質(zhì)的折疊工作,。研究人員推測，這使得蛋白無法得到合適的折疊，隨著細胞內(nèi)氧氣水平的下降和波動,，錯誤折疊的蛋白就會積聚起來,。Veasey表示，這是首次在細胞水平上發(fā)現(xiàn)內(nèi)質(zhì)網(wǎng)與睡眠窒息有關(guān),。
進一步的研究發(fā)現(xiàn),，內(nèi)質(zhì)網(wǎng)表面的感受蛋白能被內(nèi)部的錯誤折疊蛋白激活。研究人員此次關(guān)注的是一個名為PERK的蛋白,，當PERK蛋白被激活后,，有兩種情況可能會發(fā)生——細胞要么采取路徑修補自己，要么毀滅自己,。具體采取哪一種路徑,，取決于細胞原初的健康狀況。
如果睡眠窒息患者擁有健康的細胞,，細胞就會采取修補的路徑,。它們會激活另一種名為eIF-2alpha的分子，這種分子會激活抗氧化劑等有用分子來降解錯誤折疊的蛋白,。
然而,，如果細胞本來就是不健康的，PERK路徑同樣能夠激活一些分子,，使得細胞開啟凋亡和死亡路徑,。Veasey說：“在這種情況下，患者有可能損失運動神經(jīng)元,，最終會惡化睡眠窒息癥狀,，因為僅存的神經(jīng)元在睡眠喘息時已經(jīng)受到了很大的壓迫。”
一種名為salubrinal的藥物能夠使eIF-2alpha保持活性,，從而預(yù)防細胞走向死亡路徑,。但是salubrinal是一把雙刃劍——適量能保持細胞健康,，過量就會關(guān)閉所有的蛋白質(zhì)合成,，而這會產(chǎn)生很高的毒性。
研究小組目前正在改變小鼠的飲食以期提高eIF-2alpha路徑的活性,。Veasey說：“這項研究顯示了哪種路徑對于睡眠窒息的治療是重要的,。在salubrinal之外，我們需要找到新的治療方案,。如果最終我們能夠找到保護內(nèi)質(zhì)網(wǎng)的方法,，睡眠窒息也許就能得到緩解。”（科學(xué)網(wǎng) 梅進/編譯）
生物谷推薦原始出處：
（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: [email protected]
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.
