PERK通路在内质网应激诱导的中脑多巴胺能神经元死亡中作用  

Role of PERK pathway in the death of midbrain dopaminergic neurons induced by endoplasmic reticulum stress

作　　者：杨璇 郑佳音 王昕宇 于佳[1] Yang Xuan;Zheng Jiayin;Wang Xinyu;Yu Jia(Institute of Geriatrics and Rehabilitation,Beijing Geriatric Hospital,Beijing 100095,China)

机构地区：[1]北京老年医院老年医学基础研究中心,北京100095

出　　处：《脑与神经疾病杂志》2024年第1期12-16,共5页Journal of Brain and Nervous Diseases

基　　金：国家自然科学基金资助项目(82071438);北京市百千万人才工程资助项目(2017002);北京老年医院老年医学科研专项(2022bjlnyy-qh-1,2020bjlnyy-自-3)。

摘　　要：目的 探讨PERK通路在内质网应激诱导的中脑多巴胺能神经元变性死亡中的作用。方法 利用小鼠原代培养成纤维细胞,应用Western blot和免疫荧光染色法,观察内质网应激诱导剂毒胡萝卜素(thapsigargin)对PERK通路的激活,利用小鼠原代培养中脑多巴胺能神经元,应用TH免疫荧光染色法对存活的中脑多巴胺能神经元进行计数,以观察PERK抑制剂GSK2606414对长时程Thapsigargin处理诱导的中脑多巴胺能神经元死亡的影响。结果 在Thapsigargin处理后的原代成纤维细胞中p-PERK、p-eIF2α、ATF4水平均显著升高,Thapsigargin诱导中脑多巴胺能神经元死亡,PERK抑制剂GSK2606414可显著减少长时程Thapsigargin处理诱导的中脑多巴胺能神经元死亡。结论 内质网应激激活PERK通路;长时程内质网应激导致中脑多巴胺能神经元死亡,抑制PERK通路的激活可以缓解长时程内质网应激导致的中脑多巴胺能神经元死亡,PERK通路参与了长时程内质网应激导致的中脑多巴胺能神经元变性死亡。Objective To explore the role of PERK pathway in the death of midbrain dopaminergic neurons induced by endoplasmic reticulum(ER)stress.Methods Western blot and immunofluorescence staining were used to observe the activation of PERK pathway induced by endoplasmic reticulum stress inducer thapsigargin in primary cultured fibroblasts.Cell counting of surviving midbrain dopaminergic neurons after TH immunofluorescence staining was applied to observe the effect of PERK inhibitor GSK2606414 on midbrain dopaminergic neuron death induced by prolonged thapsigargin treatment.Results The level of p-PERK,p-eIF2αand ATF4 significantly increased in thapsigargin treated primary cultured fibroblasts.Thapsigargin treatment leads to death of midbrain dopaminergic neurons.PERK inhibitor GSK2606414 can significantly reduce the death of midbrain dopaminergic neurons induced by prolonged thapsigargin treatment.Conclusion ER stress induced the activation of PERK pathway.Prolonged ER stress leads to the death of midbrain dopaminergic neurons.Inhibiting the activation of PERK pathway can alleviate the death of midbrain dopaminergic neurons caused by prolonged ER stress.PERK pathway is involved in the degeneration of midbrain dopaminergic neurons induced by prolonged ER stress.

关 键 词：中脑多巴胺能神经元 内质网应激 未折叠蛋白反应 PERK通路 帕金森病 

分 类 号：R742.5[医药卫生—神经病学与精神病学]