外源性多巴胺对SH-SY5Y分化细胞毒性作用机制的差异蛋白质组学研究
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摘要
帕金森病( Parkinson’s s disease , PD )是中老年人常见慢性进行性中枢神经系统退行性疾病,于1817年由英国医师James B Parkinson首先报道。PD的发病机制至今仍未完全明了,多数人认为PD是遗传因素和环境因素共同作用的结果。近来的研究发现,PD与蛋白质错误折叠与蛋白质聚集、线粒体功能障碍和氧化应激过度、泛素蛋白酶体系统功能障碍和蛋白分解障碍、兴奋性毒性和钙的细胞毒作用、免疫学异常和年龄老化、细胞凋亡、多聚ADP核糖聚合酶过度活化等诸多因素有关。这些因素相互作用形成恶性循环,最终导致多巴胺能神经细胞死亡。内源性及外源性神经毒素启动黑质多巴胺能神经元变性、死亡并最终导致PD的假说长期以来一直受到研究者的重视。外源性和内源性多巴胺作为嗜神经毒素能够特异性损害中枢多巴胺能神经元这一作用已经得到公认。
尽管PD的病因尚不完全清楚,但是多数学者认为多巴胺能神经元内氧化应激的加重和线粒体功能障碍是导致这种疾病的中心环节。PD患者存在线粒体复合体Ι的缺陷,这可能是细胞氧化应激加重的原因或结果。研究表明,环境和遗传因素都会使多巴胺能神经元对年龄相关的氧化应激和能量缺乏的加重更加敏感。氧化应激被认为是PD患者黑质神经元死亡的主要因素。
本研究应用维甲酸相继佛波酯诱导SH-SY5Y细胞分化为具有神经元表现型特点的细胞,并首次采用差异凝胶电泳(DIGE)和质谱(MS)技术分析了维甲酸相继佛波酯诱导SH-SY5Y细胞分化的蛋白质组改变,在蛋白质组学的水平上验证了维甲酸相继佛波酯诱导SH-SY5Y分化细胞获得类神经元的特性。进一步,在外源性多巴胺诱导SH-SY5Y分化细胞PD模型的基础上,检测了外源性多巴胺对SH-SY5Y分化细胞的毒性作用。分别提取分化对照组SH-SY5Y细胞及100μmol/L多巴胺处理24小时的分化毒性组SH-SY5Y细胞的细胞总蛋白,应用荧光差异凝胶电泳(DIGE)技术获得蛋白点的差异表达信息,运用质谱(MS)技术鉴定出差异蛋白质。结果显示在分化毒性组MTT法检测到细胞存活率降低,Hoechst33342荧光染色观察到细胞凋亡的形态学改变,表明多巴胺能够诱导SH-SY5Y分化细胞凋亡;质谱鉴定出差异蛋白点10个,分别为:(1)与蛋白质折叠和转运功能有关的分子伴侣蛋白和(或)分子伴侣样蛋白:葡萄糖调节蛋白75、葡萄糖调节蛋白78、脯氨酰-4-羟化酶β亚单位、14-3-3蛋白和蛋白质二硫键异构酶相关的蛋白质;(2)与蛋白质运输功能有关的细胞骨架蛋白:α-微管蛋白泛素链、β-肌动蛋白和角蛋白9;(3)与线粒体功能和物质代谢相关的蛋白:ATP合成酶β亚基;(4)与信号转导相关的蛋白:膜联蛋白A5。它们分别与氧化应激、线粒体损伤、内质网应激、代谢和细胞对损伤的防御反应相关。这些结果为进一步探索PD的发病机制提供了有价值的新线索,也可能有助于发现PD药物治疗的新候选靶点。
Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of dopamine neurons in the substantia nigra,decreased striatal dopamine level, and the presence of eosinophilic inclusions called Lewy body in the cytoplasm of the spared neurons. The etiology and pathogenesis of PD have not been fully elucidated till now. Growing evidences suggest that the oxidative stress and the mitochondrial dysfunction are involved in the etiopathogenesis of PD.
Dopamine (DA) is an essential neurotransmitter under physiological condition and is also an endogenous or exogenous neurotoxin. Reactive oxygen species (ROS) are produced in the course of normal and pathological metabolic DA oxidation, including auto-oxidation or enzyme-catalyzed reaction or both of them. Because of their high reactivity, accumulation of ROS beyond the immediate needs of the cell may affect cellular structure and functional integrity, by bringing about oxidative degradation of critical molecules, such as the DNA, proteins and lipids, resulting in oxidative stress. Recently, many evidences from experiments and postmortem of familial and sporadic PD display that the oxidative damage exists in the dopaminergic neurons of the substantia nigra pars compacta. The oxidative stress and mitochondrial dysfunction result in the accumulation of abnormal proteins in affected cells, the defects of cell function and even cell death. Oxidative stress and mitochondrial dysfunction may be the unifying pathway of various types of PD.
Up to now, the toxic effects of DA on important protein molecules in PD patients and PD models have not been fully understood. To explore the mechanisms of DA toxicity at protein level, present study had performed the followed experiments: 1. applied RA and TPA in succession to induce the differentiation of SH-SY5Y cells; 2. applied exogenous DA to differentiated SH-SY5Y cells to evaluated the toxicity of DA on morphology, viability, and apoptosis; 3. applied DIGE and MALDI-TOF MS to identify differentially expressed proteins in differentiation course of SH-SY5Y; 4. applied DIGE and MALDI-TOF MS to identify differentially expressed proteins in exogenous DA-treated differentiated SH-SY5Y cells.
In present study, administration of RA for 72h and TPA for additional 72h successfully induced the differentiation of SH-SY5Y cells. Compared to undifferentiated SH-SY5Y cells which have not or have shorter processes, marked extension of processes was observed in differentiated SH-SY5Y cells. The differentiated SH-SY5Y cells obtained typical neuronal phenotype.
In present study, exogenous dopamine was added to differentiated SH-SY5Y cells. The viability of the cells was assayed by MTT and the apoptotic rate of the cells was measured by Hoechst33342 staining after incubation at different-concentration of dopamine for different period. In spite of its protective effect at low does (50μmol/L), DA was toxic at higher concentration (100μmol/L～500μmol/L). The viability of differentiated SH-SY5Y cells decreased with the prolonged treatment time and the increased dose of dopamine. The apoptotic rate of differentiated SH-SY5Y cells increased with the prolonged treatment time and the increased dose of dopamine.
In present study, DIGE and MALDI-TOF MS were applied to identify differentially expressed proteins in differentiation course of SH-SY5Y. Three significantly up-regulated proteins were confidently identified including tubulin alpha1 (α-tubulin 1), laminin-binding protein (LBP), and GTP-binding regulatory alpha2 inhibitory subunit (Galphai2). The significantly up-regulation ofα-tubulin 1, LBP, and Galphai2 may involve in the differentiation of SH-SY5Y cells characterized by marked extension of neuronal-like processes.
In present study, DIGE and MALDI-TOF MS were applied to identify differentially expressed proteins in differentiated SH-SY5Y treated by exogenous DA. A total of ten significantly changed proteins (of which, seven was increased and three was decreased) were unequivocally identified, including glucose-regulated protein 78 (GRP78), glucose-regulated protein 75 (GRP75), 14-3-3 zeta, prolyl-4-hydroxylase beta subunit (P4HB), protein disulfide isomerase-related protein (PDI),tubulin alpha- ubiquitous chain,β-actin (ACTB), keratin9 (KRT9), ATP synthase beta subunit (Fi- ATPase) and annexinA5. The significantly changed proteins involve in molecular chaperones, cytoskeletons, energy metabolism, and apoptosis.
For the first time, present research analyzed and identified the changes at the protein level in the PD model induced by DA in differentiated SH-SY5Y cells. Among the identified differential proteins, tubulin alpha-ubiquitous chain,β-actin and keratin9, have not be reported in previous studies in the PD model induced by DA. These findings provide new valuable clues for future PD study and these proteins may become the new candidate targets of medicine treatment.
尽管PD的病因尚不完全清楚,但是多数学者认为多巴胺能神经元内氧化应激的加重和线粒体功能障碍是导致这种疾病的中心环节。PD患者存在线粒体复合体Ι的缺陷,这可能是细胞氧化应激加重的原因或结果。研究表明,环境和遗传因素都会使多巴胺能神经元对年龄相关的氧化应激和能量缺乏的加重更加敏感。氧化应激被认为是PD患者黑质神经元死亡的主要因素。
本研究应用维甲酸相继佛波酯诱导SH-SY5Y细胞分化为具有神经元表现型特点的细胞,并首次采用差异凝胶电泳(DIGE)和质谱(MS)技术分析了维甲酸相继佛波酯诱导SH-SY5Y细胞分化的蛋白质组改变,在蛋白质组学的水平上验证了维甲酸相继佛波酯诱导SH-SY5Y分化细胞获得类神经元的特性。进一步,在外源性多巴胺诱导SH-SY5Y分化细胞PD模型的基础上,检测了外源性多巴胺对SH-SY5Y分化细胞的毒性作用。分别提取分化对照组SH-SY5Y细胞及100μmol/L多巴胺处理24小时的分化毒性组SH-SY5Y细胞的细胞总蛋白,应用荧光差异凝胶电泳(DIGE)技术获得蛋白点的差异表达信息,运用质谱(MS)技术鉴定出差异蛋白质。结果显示在分化毒性组MTT法检测到细胞存活率降低,Hoechst33342荧光染色观察到细胞凋亡的形态学改变,表明多巴胺能够诱导SH-SY5Y分化细胞凋亡;质谱鉴定出差异蛋白点10个,分别为:(1)与蛋白质折叠和转运功能有关的分子伴侣蛋白和(或)分子伴侣样蛋白:葡萄糖调节蛋白75、葡萄糖调节蛋白78、脯氨酰-4-羟化酶β亚单位、14-3-3蛋白和蛋白质二硫键异构酶相关的蛋白质;(2)与蛋白质运输功能有关的细胞骨架蛋白:α-微管蛋白泛素链、β-肌动蛋白和角蛋白9;(3)与线粒体功能和物质代谢相关的蛋白:ATP合成酶β亚基;(4)与信号转导相关的蛋白:膜联蛋白A5。它们分别与氧化应激、线粒体损伤、内质网应激、代谢和细胞对损伤的防御反应相关。这些结果为进一步探索PD的发病机制提供了有价值的新线索,也可能有助于发现PD药物治疗的新候选靶点。
Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of dopamine neurons in the substantia nigra,decreased striatal dopamine level, and the presence of eosinophilic inclusions called Lewy body in the cytoplasm of the spared neurons. The etiology and pathogenesis of PD have not been fully elucidated till now. Growing evidences suggest that the oxidative stress and the mitochondrial dysfunction are involved in the etiopathogenesis of PD.
Dopamine (DA) is an essential neurotransmitter under physiological condition and is also an endogenous or exogenous neurotoxin. Reactive oxygen species (ROS) are produced in the course of normal and pathological metabolic DA oxidation, including auto-oxidation or enzyme-catalyzed reaction or both of them. Because of their high reactivity, accumulation of ROS beyond the immediate needs of the cell may affect cellular structure and functional integrity, by bringing about oxidative degradation of critical molecules, such as the DNA, proteins and lipids, resulting in oxidative stress. Recently, many evidences from experiments and postmortem of familial and sporadic PD display that the oxidative damage exists in the dopaminergic neurons of the substantia nigra pars compacta. The oxidative stress and mitochondrial dysfunction result in the accumulation of abnormal proteins in affected cells, the defects of cell function and even cell death. Oxidative stress and mitochondrial dysfunction may be the unifying pathway of various types of PD.
Up to now, the toxic effects of DA on important protein molecules in PD patients and PD models have not been fully understood. To explore the mechanisms of DA toxicity at protein level, present study had performed the followed experiments: 1. applied RA and TPA in succession to induce the differentiation of SH-SY5Y cells; 2. applied exogenous DA to differentiated SH-SY5Y cells to evaluated the toxicity of DA on morphology, viability, and apoptosis; 3. applied DIGE and MALDI-TOF MS to identify differentially expressed proteins in differentiation course of SH-SY5Y; 4. applied DIGE and MALDI-TOF MS to identify differentially expressed proteins in exogenous DA-treated differentiated SH-SY5Y cells.
In present study, administration of RA for 72h and TPA for additional 72h successfully induced the differentiation of SH-SY5Y cells. Compared to undifferentiated SH-SY5Y cells which have not or have shorter processes, marked extension of processes was observed in differentiated SH-SY5Y cells. The differentiated SH-SY5Y cells obtained typical neuronal phenotype.
In present study, exogenous dopamine was added to differentiated SH-SY5Y cells. The viability of the cells was assayed by MTT and the apoptotic rate of the cells was measured by Hoechst33342 staining after incubation at different-concentration of dopamine for different period. In spite of its protective effect at low does (50μmol/L), DA was toxic at higher concentration (100μmol/L～500μmol/L). The viability of differentiated SH-SY5Y cells decreased with the prolonged treatment time and the increased dose of dopamine. The apoptotic rate of differentiated SH-SY5Y cells increased with the prolonged treatment time and the increased dose of dopamine.
In present study, DIGE and MALDI-TOF MS were applied to identify differentially expressed proteins in differentiation course of SH-SY5Y. Three significantly up-regulated proteins were confidently identified including tubulin alpha1 (α-tubulin 1), laminin-binding protein (LBP), and GTP-binding regulatory alpha2 inhibitory subunit (Galphai2). The significantly up-regulation ofα-tubulin 1, LBP, and Galphai2 may involve in the differentiation of SH-SY5Y cells characterized by marked extension of neuronal-like processes.
In present study, DIGE and MALDI-TOF MS were applied to identify differentially expressed proteins in differentiated SH-SY5Y treated by exogenous DA. A total of ten significantly changed proteins (of which, seven was increased and three was decreased) were unequivocally identified, including glucose-regulated protein 78 (GRP78), glucose-regulated protein 75 (GRP75), 14-3-3 zeta, prolyl-4-hydroxylase beta subunit (P4HB), protein disulfide isomerase-related protein (PDI),tubulin alpha- ubiquitous chain,β-actin (ACTB), keratin9 (KRT9), ATP synthase beta subunit (Fi- ATPase) and annexinA5. The significantly changed proteins involve in molecular chaperones, cytoskeletons, energy metabolism, and apoptosis.
For the first time, present research analyzed and identified the changes at the protein level in the PD model induced by DA in differentiated SH-SY5Y cells. Among the identified differential proteins, tubulin alpha-ubiquitous chain,β-actin and keratin9, have not be reported in previous studies in the PD model induced by DA. These findings provide new valuable clues for future PD study and these proteins may become the new candidate targets of medicine treatment.
引文
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