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Title: 糖原合成酶激酶3β和内质网应激在鱼藤酮引起的SK-N-MC神经母细胞瘤细胞死亡中的作用研究
Author: 陈园园
Degree Level: 博士
Issued Date: 2008-06-09
Degree Grantor: 中国科学院上海生命科学研究院
Place of Degree Grantor: 上海生命科学研究院
Supervisor: 柯尊记
Keyword: 帕金森病 ; 鱼藤酮 ; 氧化应激 ; 糖原合成酶激酶3β(GSK3β) ; 内质网应激
Alternative Title: GSK3β and endoplasmic reticulum stress mediate rotenone-induced death of SK-N-MC neuroblastoma cells
Major: 神经生物学
Abstract: 帕金森病是一种因中脑黑质多巴胺能神经元减少导致的以运动障碍为主要表现的神经退行性疾病。鱼藤酮通过抑制细胞线粒体复合物I可特异性地引起动物帕金森病样症状,是建立帕金森病细胞和动物模型的常用药物。通常认为鱼藤酮通过抑制线粒体电子传递链、引起氧化损伤而杀伤细胞。但氧化损伤不能解释低剂量鱼藤酮导致多巴胺能神经元死亡的现象。糖原合成酶激酶3β(GSK3β)是一种丝/苏氨酸蛋白激酶,功能广泛,近年的研究发现,其在神经退行性疾病中亦发挥作用。我们的研究发现,低剂量鱼藤酮引起的SK-N-MC神经母细胞瘤细胞死亡先于氧化损伤,且抗氧化剂不能保护细胞。进一步的研究显示,低剂量鱼藤酮可以使GSK3β第9位丝氨酸的磷酸化减少,第216位酪氨酸的磷酸化增多而激活GSK3β介导的细胞死亡通路。抑制GSK3β的活性可以部分减少鱼藤酮引起的SK-N-MC细胞死亡。低剂量鱼藤酮还可引起SK-N-MC细胞表达内质网应激反应的几种标志分子,并通过PERK、eIF2α磷酸化通路诱导细胞死亡。用eIF2α siRNA选择性抑制eIF2α的表达可以明显降低鱼藤酮对细胞的毒性。而内质网应激诱导物毒胡萝卜素和衣霉素并不影响GSK3β的活性,说明鱼藤酮引起的内质网应激与其对GSK3β活性的调节无关。同时抑制GSK3β的活性和eIF2α的表达可以更明显地减少鱼藤酮引起的细胞死亡。因此,我们认为GSK3β激活和内质网应激是低剂量鱼藤酮引起的神经母细胞瘤细胞死亡的主要原因。这一结果提示,GSK3β激活和内质网应激可能是帕金森病病人脑内多巴胺能神经元死亡的分子细胞机制。
English Abstract: Parkinson's disease (PD) is a neurodegenerative disease induced by the loss of substantia nigra dopaminergic neurons, and often impairs the sufferer's motor system. Rotenone, an environmental toxin that inhibits mitochondrial complex I, has been used to induce experimental Parkinsonism in animals and cell cultures. We investigated the mechanism underlying rotenone-induced death of SK-N-MC neuroblastoma cells. Rotenone-induced cell death preceded intracellular accumulation of reactive oxygen species, and antioxidants failed to protect cells, indicating that oxidative stress was minimally involved in rotenone-induced death of SK-N-MC cells. Glycogen synthase kinase 3β (GSK3β), a multifunctional serine/threonine kinase, has been implicated in the pathogenesis of neurodegeneration. We showed that rotenone activated GSK3β by enhancing its phosphorylation at tyrosine 216 while inhibiting phosphorylation at serine 9. Inhibitors of GSK3β and dominant negative (kinase deficient) GSK3β partially protected SK-N-MC cells against rotenone cytotoxicity. Rotenone also induced endoplasmic reticulum (ER) stress which was evident by an increase in phosphorylation of PERK, PKR, and eIF2α as well as the expression of GRP78. Rotenone had a modest effect on the expression of CHOP. An eIF2α siRNA significantly reduced rotenone cytotoxicity. ER stress was experimentally induced by tunicamycin and thapsigargin, but tunicamycin/thapsigargin did not activate GSK3β in SK-N-MC cells. Down-regulation of eIF2α also offered partial protection against rotenone cytotoxicity. Combined treatment of GSK3β inhibitors and eIF2α siRNA provided much greater protection than either treatment alone. Taken together, the results suggest that GSK3β activation and ER stress contribute separately to rotenone cytotoxicity.
Language: 中文
Content Type: 学位论文
URI: http://ir.sibs.ac.cn/handle/331001/2378
Appears in Collections:神经所(总)_学位论文

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Recommended Citation:
糖原合成酶激酶3β和内质网应激在鱼藤酮引起的SK-N-MC神经母细胞瘤细胞死亡中的作用研究.陈园园[d].中国科学院上海生命科学研究院,2008.20-25
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