G蛋白偶联受体激酶5在帕金森病模型中的表达及其在帕金森病中的作用研究
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摘要
G蛋白偶联受体激酶5在帕金森病模型中的表达及作用
帕金森病是一种神经退行性疾病,其发病率仅次于阿尔茨海默病。以震颤、僵直、姿势平衡障碍和运动功能障碍为临床特点,并且以黑质纹状体多巴胺神经元消失以及残存的黑质多巴胺细胞胞浆中出现路易小体(Lewy bodies, LBs)小体为病理特点。GRKs(G protein-coupled receptor kinases)是G蛋白偶联受体激酶,主要的功能是对G蛋白偶联受体(G protein-coupled receptor, GPCRs)进行磷酸化,从而介导GPCR的脱敏反应。GPCR被磷酸化后,抑制样蛋白(Beta arrestins)与其结合,使其与G蛋白脱偶联并发生内吞,进而调控细胞内信号传递的级联反应。而GRKs除了具有通过GPCR发挥G蛋白偶联受体激酶的作用外,最近发现GRKs同时存在有一些非受体底物,如tubulin, synucleins和核蛋白体P2蛋白等。最近Shigeki Arawaka等人发现在路易小体中存在有GRKs家族的GRK5蛋白。而且通过实验证实了GRK5与a-Synuclein存在共定位,并有力地证明了GRK5可以对a-Synuclein的第129位丝氨酸进行磷酸化。我们通过建立过表达a-Synuclein的帕金森病细胞模型和动物模型,研究GRK5在帕金森病中的表达变化以及GRK5在帕金森病中的可能作用,为发现帕金森病的发病机制和探索更好的治疗方法提供新的方向。
本研究主要包括以下两个部分的实验内容：
1帕金森病a-Synuclein转基因小鼠和细胞模型中G蛋白偶联受体激酶5的表达以及亚细胞水平的GRK5蛋白表达变化：采用免疫印迹和实时荧光定量PCR技术对具有不同的人a-Synuclein (ha-syn)表达水平的帕金森病a-Synuclein转基因模型小鼠以及3月龄、6月龄和9月龄人a-Synuclein野生型高表达组转基因小鼠脑组织进行GRK5的RNA和蛋白水平检测,与同窝阴性对照小鼠进行比较。同时在建立的a-Synuclein稳定转染细胞系中进行GRK5的表达水平检测并采用免疫荧光技术观察GRK5蛋白的亚细胞水平表达变化。研究结果显示,GRK5蛋白的表达水平随着a-Synuclein的表达升高而升高,并且发现GRK5蛋白在过表达a-Synuclein的细胞以及转基因小鼠的脑组织中的细胞核以及细胞浆内均表达增加。
2 G蛋白偶联受体激酶5的胞浆内以及胞核内功能研究：应用免疫印迹技术、免疫组织化学技术、HDAC活性检测技术、染色体免疫共沉淀技术以及shRNA干扰技术对a-Synuclein稳定转染细胞系和人a-Synuclein野生型高表达组转基因小鼠脑组织增高的胞浆以及胞核内GRK5蛋白的功能进行研究。研究结果显示,胞浆中的GRK5蛋白具有除磷酸化α-Synuclein 129位丝氨酸以外的其他作用,胞核中的GRK5蛋白通过影响组蛋白去乙酰化酶的活性对bcl2基因的转录和表达进行调控。
综上所述,帕金森病中GRK5的表达增加可能通过增加组蛋白去乙酰化酶活性抑制凋亡相关基因bcl2的转录和表达发挥作用。这一发现对于充分理解GRK5的功能作用以及更好的理解帕金森病的发病机制具有重要意义。
Up-regulation of G-protein-coupled receptor kinase 5 in the a-Synuclein over-expression mouse model and cell model of Parkinson's disease Regulates Gene Transcription in Nucleus
Parkinson's disease is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies (LBs). a-Synuclein as the major component of LBs was identified to be phosphorylated at Ser-129 (pS129-a-synuclein) in LBs. GRKs as members of serine/threonine protein kinases family phosphorylate activated GPCRs and thereby result in these receptors' desensitization. They play the critical role in cellular signaling. But the function of GRKs is not limited to the mediation of GPCR desensitization. Recently, some nonreceptor substrates of GRKs were found, including tubulin, synucleins and the ribosomal protein P2. Recently GRK5 has been correlated to the pathogenesis of Parkinson's disease, a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies (LBs).α-Synuclein as the major component of LBs was identified to be phosphorylated at Ser-129 (pS129-a-synuclein) in LBs. Recent event showed that phosphorylation at Ser-129 ofα-synuclein is essential for its toxicity to dopaminergic neurons.GRK5 was reported to phosphorylate a-synuclein at Ser-129 and in the following study GRK5 was detected to accumulate in Lewy bodies and colocalize withα-synuclein in the pathological structures of the brains of sPD patients. These evidents proved that GRK5 was involved in the pathogenesis of Parkinson's disease for the modification ofα-synuclein in LBs. In addition to the function of phosphorylation at Ser-129 ofα-synuclein, GRK5 has been found as a histone deacetylase kinase in the nucleus of cardiomyocytes. The DNA-binding nuclear localization sequence(NLS) contained in GRK5 and the activity of HDAC kinase detected in GRK5 make us explore the more potential function of GRK5 in parkinson's disease.
We developed the human a-synuclein transgenic mice and the stable transfected humana-synuclein SHSY5Y cell lines to investigate the alters of GRK5 expression level and then determined whether it effects the activity of HDAC in Parkinson's disease. If it does, we want to quest the goal genes regulated by GRK5. Two parts were included in the research:
1 The expression level of GRK5 protein in the alpha-synuclein over-expression mouse model and cell model of Parkinson's disease and the distribution of the increased GRK5 protein:The mRNA and protein expression levels of GRK5 in various Parkinson's disease a-synuclein transgenic mice groups and 3m,6m and 9m hα-synuclein transgenic mice were measured by western blotting and real time PCR. At the same time, we used western blotting and Immunocytofluorescence to observe the distribution of the increased GRK5 protein. The results show to us, the expression level of GRK5 was elevated in Parkinson's diseaseα-synuclein transgenic mice and in the stable transfectedα-synuclein cell lines. And GRK5 protein accumulates not only in the cytosol but also in the nucleus.
2 The function of GRK5 in cytosol and in nucleus:Western blotting, Immunohistoche-mistry, HDAC assay, ChIP and RNAi technique were used to detect the function of GRK5 in cytosol and in nucleus. The results suggest potential cytosolic GRK5 function, rather than alpha synuclein phosphorylative events, appears as the underlying mechanism of Parkinson's disease. Nuclear accumulation of GRK5 inhibits blc2 transcription and expression by enhancing the activity of HDAC and the opposite results are obtained by GRK5 repressed through shRNA.
To sum up, we report in this study that overexpression of alpha synuclein in vivo or in vitro induces increase of cytosolic and nuclear GRK5 and we reveal an unexpected role for GRK5 in the regulation of apoptosis-or cell cycle-related genes at the first time. These results suggest that GRK5 has more extensive effects in the Parkinson's disease.
帕金森病是一种神经退行性疾病,其发病率仅次于阿尔茨海默病。以震颤、僵直、姿势平衡障碍和运动功能障碍为临床特点,并且以黑质纹状体多巴胺神经元消失以及残存的黑质多巴胺细胞胞浆中出现路易小体(Lewy bodies, LBs)小体为病理特点。GRKs(G protein-coupled receptor kinases)是G蛋白偶联受体激酶,主要的功能是对G蛋白偶联受体(G protein-coupled receptor, GPCRs)进行磷酸化,从而介导GPCR的脱敏反应。GPCR被磷酸化后,抑制样蛋白(Beta arrestins)与其结合,使其与G蛋白脱偶联并发生内吞,进而调控细胞内信号传递的级联反应。而GRKs除了具有通过GPCR发挥G蛋白偶联受体激酶的作用外,最近发现GRKs同时存在有一些非受体底物,如tubulin, synucleins和核蛋白体P2蛋白等。最近Shigeki Arawaka等人发现在路易小体中存在有GRKs家族的GRK5蛋白。而且通过实验证实了GRK5与a-Synuclein存在共定位,并有力地证明了GRK5可以对a-Synuclein的第129位丝氨酸进行磷酸化。我们通过建立过表达a-Synuclein的帕金森病细胞模型和动物模型,研究GRK5在帕金森病中的表达变化以及GRK5在帕金森病中的可能作用,为发现帕金森病的发病机制和探索更好的治疗方法提供新的方向。
本研究主要包括以下两个部分的实验内容：
1帕金森病a-Synuclein转基因小鼠和细胞模型中G蛋白偶联受体激酶5的表达以及亚细胞水平的GRK5蛋白表达变化：采用免疫印迹和实时荧光定量PCR技术对具有不同的人a-Synuclein (ha-syn)表达水平的帕金森病a-Synuclein转基因模型小鼠以及3月龄、6月龄和9月龄人a-Synuclein野生型高表达组转基因小鼠脑组织进行GRK5的RNA和蛋白水平检测,与同窝阴性对照小鼠进行比较。同时在建立的a-Synuclein稳定转染细胞系中进行GRK5的表达水平检测并采用免疫荧光技术观察GRK5蛋白的亚细胞水平表达变化。研究结果显示,GRK5蛋白的表达水平随着a-Synuclein的表达升高而升高,并且发现GRK5蛋白在过表达a-Synuclein的细胞以及转基因小鼠的脑组织中的细胞核以及细胞浆内均表达增加。
2 G蛋白偶联受体激酶5的胞浆内以及胞核内功能研究：应用免疫印迹技术、免疫组织化学技术、HDAC活性检测技术、染色体免疫共沉淀技术以及shRNA干扰技术对a-Synuclein稳定转染细胞系和人a-Synuclein野生型高表达组转基因小鼠脑组织增高的胞浆以及胞核内GRK5蛋白的功能进行研究。研究结果显示,胞浆中的GRK5蛋白具有除磷酸化α-Synuclein 129位丝氨酸以外的其他作用,胞核中的GRK5蛋白通过影响组蛋白去乙酰化酶的活性对bcl2基因的转录和表达进行调控。
综上所述,帕金森病中GRK5的表达增加可能通过增加组蛋白去乙酰化酶活性抑制凋亡相关基因bcl2的转录和表达发挥作用。这一发现对于充分理解GRK5的功能作用以及更好的理解帕金森病的发病机制具有重要意义。
Up-regulation of G-protein-coupled receptor kinase 5 in the a-Synuclein over-expression mouse model and cell model of Parkinson's disease Regulates Gene Transcription in Nucleus
Parkinson's disease is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies (LBs). a-Synuclein as the major component of LBs was identified to be phosphorylated at Ser-129 (pS129-a-synuclein) in LBs. GRKs as members of serine/threonine protein kinases family phosphorylate activated GPCRs and thereby result in these receptors' desensitization. They play the critical role in cellular signaling. But the function of GRKs is not limited to the mediation of GPCR desensitization. Recently, some nonreceptor substrates of GRKs were found, including tubulin, synucleins and the ribosomal protein P2. Recently GRK5 has been correlated to the pathogenesis of Parkinson's disease, a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies (LBs).α-Synuclein as the major component of LBs was identified to be phosphorylated at Ser-129 (pS129-a-synuclein) in LBs. Recent event showed that phosphorylation at Ser-129 ofα-synuclein is essential for its toxicity to dopaminergic neurons.GRK5 was reported to phosphorylate a-synuclein at Ser-129 and in the following study GRK5 was detected to accumulate in Lewy bodies and colocalize withα-synuclein in the pathological structures of the brains of sPD patients. These evidents proved that GRK5 was involved in the pathogenesis of Parkinson's disease for the modification ofα-synuclein in LBs. In addition to the function of phosphorylation at Ser-129 ofα-synuclein, GRK5 has been found as a histone deacetylase kinase in the nucleus of cardiomyocytes. The DNA-binding nuclear localization sequence(NLS) contained in GRK5 and the activity of HDAC kinase detected in GRK5 make us explore the more potential function of GRK5 in parkinson's disease.
We developed the human a-synuclein transgenic mice and the stable transfected humana-synuclein SHSY5Y cell lines to investigate the alters of GRK5 expression level and then determined whether it effects the activity of HDAC in Parkinson's disease. If it does, we want to quest the goal genes regulated by GRK5. Two parts were included in the research:
1 The expression level of GRK5 protein in the alpha-synuclein over-expression mouse model and cell model of Parkinson's disease and the distribution of the increased GRK5 protein:The mRNA and protein expression levels of GRK5 in various Parkinson's disease a-synuclein transgenic mice groups and 3m,6m and 9m hα-synuclein transgenic mice were measured by western blotting and real time PCR. At the same time, we used western blotting and Immunocytofluorescence to observe the distribution of the increased GRK5 protein. The results show to us, the expression level of GRK5 was elevated in Parkinson's diseaseα-synuclein transgenic mice and in the stable transfectedα-synuclein cell lines. And GRK5 protein accumulates not only in the cytosol but also in the nucleus.
2 The function of GRK5 in cytosol and in nucleus:Western blotting, Immunohistoche-mistry, HDAC assay, ChIP and RNAi technique were used to detect the function of GRK5 in cytosol and in nucleus. The results suggest potential cytosolic GRK5 function, rather than alpha synuclein phosphorylative events, appears as the underlying mechanism of Parkinson's disease. Nuclear accumulation of GRK5 inhibits blc2 transcription and expression by enhancing the activity of HDAC and the opposite results are obtained by GRK5 repressed through shRNA.
To sum up, we report in this study that overexpression of alpha synuclein in vivo or in vitro induces increase of cytosolic and nuclear GRK5 and we reveal an unexpected role for GRK5 in the regulation of apoptosis-or cell cycle-related genes at the first time. These results suggest that GRK5 has more extensive effects in the Parkinson's disease.
引文
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