State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
Center for Reproductive Medicine, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China.
Cell Death Dis. 2020 Feb 18;11(2):130. doi: 10.1038/s41419-020-2312-8.
The endoplasmic reticulum (ER)-stress-induced cascade events are implicated in Parkinson's disease (PD). The discovery of drug candidates to protect dopaminergic (DA) neurons from ER-stress-induced oxidative damage is important to resolve the pathological aspects of PD and modify its progress. In this study, we found that a recently identified unfolded protein response (UPR) modulator, azoramide, showed protective effects on patient induced pluripotent stem cells-derived midbrain DA neurons with the homozygous phospholipase A2 group 6 (PLA2G6) D331Y mutant. A series of PD-related cascade events such as ER stress, abnormal calcium homeostasis, mitochondrial dysfunction, increase of reactive oxygen species, and apoptosis were observed in PLA2G6 D331Y mutant DA neurons, whereas azoramide significantly protected PLA2G6 D331Y mutant DA neurons against these events. The beneficial effects of azoramide were abolished by treatment with a cAMP-response element binding protein (CREB) inhibitor. Our results suggest that azoramide is a potential neuroprotectant against DA neuron damage via restoring ER function and the CREB signaling.
内质网（ER）应激诱导级联事件与帕金森病（PD）有关。发现能够保护多巴胺能（DA）神经元免受 ER 应激诱导的氧化损伤的药物候选物对于解决 PD 的病理方面和改变其进展非常重要。在这项研究中，我们发现最近鉴定的未折叠蛋白反应（UPR）调节剂，azoramide，对具有同型磷脂酶 A2 组 6（PLA2G6）D331Y 突变的患者诱导多能干细胞衍生的中脑 DA 神经元具有保护作用。在 PLA2G6 D331Y 突变的 DA 神经元中观察到一系列与 PD 相关的级联事件，如 ER 应激、异常钙稳态、线粒体功能障碍、活性氧增加和细胞凋亡，而 azoramide 则显著保护 PLA2G6 D331Y 突变的 DA 神经元免受这些事件的影响。用 cAMP 反应元件结合蛋白（CREB）抑制剂处理会消除 azoramide 的有益作用。我们的结果表明，azoramide 通过恢复 ER 功能和 CREB 信号通路，是一种潜在的神经保护剂，可防止 DA 神经元损伤。
