Zhao Helen, Lin Jonathan, Sieck Gary, Haddad Gabriel G
Department of Pediatrics (Respiratory Medicine), University of California, San Diego, La Jolla, CA, United States.
Department of Pathology, University of California, San Diego, La Jolla, CA, United States.
Front Neurosci. 2021 Jan 15;14:607711. doi: 10.3389/fnins.2020.607711. eCollection 2020.
Chronic mountain sickness (CMS) is a disease that potentially threatens a large segment of high-altitude populations during extended living at altitudes above 2,500 m. Patients with CMS suffer from severe hypoxemia, excessive erythrocytosis and neurologic deficits. The cellular mechanisms underlying CMS neuropathology remain unknown. We previously showed that iPSC-derived CMS neurons have altered mitochondrial dynamics and increased susceptibility to hypoxia-induced cell death. Genome analysis from the same population identified many ER stress-related genes that play an important role in hypoxia adaptation or lack thereof. In the current study, we showed that iPSC-derived CMS neurons have increased expression of ER stress markers Grp78 and XBP1s under normoxia and hyperphosphorylation of PERK under hypoxia, alleviating ER stress does not rescue the hypoxia-induced CMS neuronal cell death. Akt is a cytosolic regulator of ER stress with PERK as a direct target of Akt. CMS neurons exhibited lack of Akt activation and lack of increased Parkin expression as compared to non-CMS neurons under hypoxia. By enhancing Akt activation and Parkin overexpression, hypoxia-induced CMS neuronal cell death was reduced. Taken together, we propose that increased Akt activation protects non-CMS from hypoxia-induced cell death. In contrast, impaired adaptive mechanisms including failure to activate Akt and increase Parkin expression render CMS neurons more susceptible to hypoxia-induced cell death.
慢性高山病（CMS）是一种在海拔2500米以上长期居住期间可能威胁很大一部分高海拔人群的疾病。CMS患者患有严重的低氧血症、红细胞增多症和神经功能缺损。CMS神经病理学的细胞机制尚不清楚。我们之前表明，诱导多能干细胞（iPSC）衍生的CMS神经元具有线粒体动力学改变以及对缺氧诱导的细胞死亡敏感性增加的情况。对同一人群的基因组分析确定了许多内质网（ER）应激相关基因，这些基因在缺氧适应或缺乏适应过程中发挥重要作用。在当前研究中，我们表明，iPSC衍生的CMS神经元在常氧条件下内质网应激标志物葡萄糖调节蛋白78（Grp78）和XBP1s的表达增加，在缺氧条件下蛋白激酶RNA样内质网激酶（PERK）发生过度磷酸化，减轻内质网应激并不能挽救缺氧诱导的CMS神经元细胞死亡。Akt是内质网应激的胞质调节剂，PERK是Akt的直接靶点。与缺氧条件下的非CMS神经元相比，CMS神经元表现出Akt激活缺失和帕金蛋白（Parkin）表达未增加。通过增强Akt激活和Parkin过表达，缺氧诱导的CMS神经元细胞死亡减少。综上所述，我们提出增加Akt激活可保护非CMS神经元免受缺氧诱导的细胞死亡。相反，包括未能激活Akt和增加Parkin表达在内的适应性机制受损，使CMS神经元更容易受到缺氧诱导的细胞死亡影响。
