摘要
目标：有大量证据表明神经退行性疾病实体与分子水平的扰动直接相关。因此，ER应激介导的未折叠蛋白反应（UPR）被激活，导致真核起始因子2（eIF2α）的PERK依赖性磷酸化。因此，ATF4和CHOP蛋白的水平显着增加，其随后将UPR的适应性分支转变为促凋亡，直接导致神经元丢失和神经变性过程的启动。本研究的目的是评估PERK依赖性UPR信号通路的高度特异性小分子抑制剂的生物活性。 方法：对大鼠星形胶质细胞DI TNC1细胞系进行研究。通过蛋白质印迹技术测量p-eIF2α的水平，通过MTT测定法评估所研究化合物的细胞毒性，并使用FITC缀合的膜联蛋白V（膜联蛋白V-FITC）指示细胞凋亡和碘化丙啶（PI）以指示坏死。通过流式细胞术测量测试化合物对细胞周期进展的影响，其中分析PI标记的细胞核的DNA含量。 结果：结果，所研究的化合物LDN-0060609之一触发了对DI TNC1细胞系中eIF2α磷酸化的显着抑制。此外，我们显示化合物LDN-0060609是非细胞毒性的并且对细胞周期进展没有影响。 结论：总之，LDN-0060609可能构成针对神经退行性疾病（包括阿尔茨海默病（AD））的新型靶向治疗方法，其中发病机制和进展与PERK依赖性UPR信号传导途径的过度活化密切相关。
关键词: PERK，eIF2α，PERK抑制剂，神经变性，阿尔茨海默病，细胞凋亡。
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