突变型DJ-1蛋白对细胞线粒体功能、基因表达谱的影响和AREP基因型与表型分析
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摘要
第一部分突变型DJ-1蛋白对细胞线粒体功能和基因组表达谱的影响
DJ-1基因是常染色体隐性遗传早发性帕金森综合征(autosomalrecessive early-onset parkinsonism,AREP)的致病基因之一,目前在PD发病机制中的作用仍不清楚。前期工作中,本研究小组发现一种新的DJ-1基因突变——L10P。为探讨DJ-1基因的L10P突变在帕金森病(Parkinson's disease,PD)发病机制中的作用,我们从以下3个方面进行了研究:
1.应用G418进行稳定表达pCMV-Tag 2A-Flag、pCMV-Tag2A-Flag-DJ-1、pCMV-Tag 2A-Flag-DJ-1-L10P的HEK293单克隆细胞株的筛选,并在DNA、RNA和蛋白质三个水平上进行鉴定,证实获得稳定表达空载体、野生型DJ-1蛋白、L10P突变型DJ-1蛋白的HEK293单克隆细胞株。
2.应用流式细胞仪、分光光度计、电镜等技术对稳定表达空载体、野生型DJ-1蛋白、L10P突变型DJ-1蛋白的HEK293单克隆细胞株的生长活力、活性氧、膜电位、线粒体复合体酶Ⅰ活性及线粒体形态进行分析,结果发现与空载体组相比较,L10P突变型DJ-1组细胞内活性氧增高,细胞活力、膜电位、线粒体复合体Ⅰ活性降低,线粒体含量减少,出现线粒体肿胀,甚至线粒体空泡变性,特别是在鱼藤酮的诱导下更明显;野生型DJ-1组细胞内野生型DJ-1组中活性氧均较低,细胞活力、膜电位、线粒体复合体Ⅰ活性均较高,特别是在鱼藤酮的诱导下更明显,提示L10P突变型DJ-1蛋白存在细胞毒性作用,丧失了野生型DJ-1蛋白的抗氧化应激能力,并对线粒体的正常功能存在影响。
3.为明确L10P突变型DJ-1蛋白是否可能通过转录调控活性的变化导致相关基因表达异常而参与PD的发病机制,我们应用基因表达微珠芯片对稳定表达空载体、野生型DJ-1蛋白、L10P突变型DJ-1蛋白的HEK293单克隆细胞株进行差异表达基因筛选,结果发现与空载体组比较,野生型DJ-1组有14个基因表达上调,28个基因表达下调;L10P突变型DJ-1组有14个基因表达上调,9个基因表达下调。L10P突变型DJ-1组与野生型型DJ-1组比较发现有59个基因表达上调,27个基因表达下调。进一步分析发现这些表达差异基因分别参与信号转导、细胞粘附、基因转录调控、细胞周期、蛋白修饰、细胞凋亡、氧化应激等生物学过程,提示L10P突变型DJ-1蛋白可能通过直接或间接方式对这些差异基因进行表达调控,进而影响这些通路的正常功能,参与PD的发病机制。
第二部分常染色体隐性遗传早发性帕金森综合征基因型与表型分析
AREP有3种基因型(PARK2、PARK6和PARK7),致病基因分别是:parkin、PINK1和DJ-1基因。为探讨AREP的基因型与表型是否相关,我们从以下3个方面进行了研究:
1.建立了应用实时荧光定量PCR技术检测parkin基因外显子重排突变的技术平台和应用DNA直接测序检测ATP13A2基因突变的技术平台,完善了30个AREP家系的parkin、PINK1、DJ-1和ATP13A2基因的突变分析,结果发现在该组AREP家系中parkin、PINK1、DJ-1和ATP13A2基因的突变率分别为46.7%、6.7%、3.3%、0%,而PINK1和DJ-1双基因突变的频率为3.3%。
2.分别对一个携带parkin、PINK1、DJ-1基因突变的AREP家系进行以~(11)C-CFT标记多巴胺转运体蛋白的PET分析,发现所有的患者多巴胺转运体显像信号明显减低,与临床症状严重程度呈负相关;对家系杂合子的研究发现parkin、PINK1基因突变携带者多巴胺转运体显像信号双侧对称性减低,而DJ-1基因突变携带者多巴胺转运体显像信号双侧对称,无明显减低,提示parkin和PINK1基因的杂合子突变可能具有致病性。
3.详细分析了30个AREP家系患者的临床资料,并根据基因突变检测结果对各亚型进行临床分析,结果未发现具有明显基因型指向的临床表型。
PartⅠThe effect of mutated DJ-1 protein to cellular mitochondrial function and expression profiles of genes
DJ-1 gene is one of the pathogenic genes that are responsible for autosomal recessive early-onset parkinsonism(AREP)and its effect to the pathogenesis of Parkinson's disease(PD)is still unknown.In our prophase works,a novel DJ-1 mutation(L10P)was found.To elucidate the effect of L10P mutated DJ-1 protein to the pathogenesis of PD,we investigated the function of DJ-1 on the following three aspects:
1.To generate HEK293 monoclone cell lines which are stably expressing Flag-tagged wild-type and L10P mutated DJ-1 protein, G418(800μg/ml)was used when pCMV-Tag 2A-Flag-DJ-1、pCMV-Tag 2A-Flag-DJ-1-L10P were transfected.To confirm the HEK293 monoclone cell lines which can stably express Flag-tagged wild-type and L10P mutated DJ-1 protein,we identified the transfected plasmids were conformed in the gDNA,could be transcripted in the RNA level and expressed protein with the Flag tag.We got the HEK293 monoclone cell lines which were stably expressing empty vector,Flag-tagged wild-type and L10P mutated DJ-1 protein successfully.
2.Using spectrophotometer,flow cytometry and electron microscope to investigate cell viability,reactive oxygen species(ROS), mitochondrial transmembrane potential,complexⅠactivity and mitochondfial morphous of the HEK293 monoclone cell lines which are stably expressing wild-type and L10P mutated DJ-1 protein.Compared with the cell lines expressing empty vector,we found the ROS was increased,the cell viability,mitochondrial transmembrane potential, complexⅠactivity were reduced in these cell expressing L10P mutated DJ-1 protein.We also found mitochondria in these cells were swelling and some mitochondria were vacuolar degeneration.These phenomena were more obvious when rotenone was used.But in the cell expressing wild-type DJ-1,ROS was lower,the cell viability,mitochondrial transmembrane potential,complexⅠactivity were higher than other cell lines,especially under the induction of rotenone.It suggested that L10P mutated DJ-1 protein probably loss the ability of anti-oxidative stress and affect the normal function of mitochondria.
3.To identify genes for which expressions are abnormally regulated by L10P mutated DJ-1 protein,DNA microarray analyses were carried out using HEK293 monoclone cell lines which are stably expressing empty vector,wild-type and L10P mutated DJ-1 protein.Compared with the cell lines expressing empty vector,we found expression levels of 14 and 28 genes in expressing wild-type DJ-1 protein cells and expression levels of 14 and 9 genes in expressing L10P mutated DJ-1 protein cells increased and decreased,respectively.Compared with the cell lines expressing wild-type DJ-1 protein,we found expression levels of 59 and 27 genes in expressing L10P mutated DJ-1 protein cells increased and decreased,respectively.These genes were classified genes related to signal transduction,cell adhesion,regulation of transcription,regulation of cell cycle,protein modification,apoptosis,oxidative stress and neurotoxicity.It suggested that L10P mutated DJ-1 protein probably affects the normal function of these pathways via changing these associated gene express level to participate the pathogenesis of PD.
PartⅡThe correlation analysis of genotype and phenotype of autosomal recessive early-onset parkinsonism
Three loci,for autosomal recessive early-onset parkinsonism(AREP) have been mapped thus far(PARK2,PARK6 and PARK7)and all the three pathogenic genes have been cloned,that is parkin,PINK1 and DJ-1. To elucidate the correlation between genotype and phenotype of AREP, we investigated the following three aspects:
1.After establishing the methods of real-time PCR to screen parkin gene rearrangement and DNA direct sequencing to detect the ATP13A2 gene mutation,we consummated the mutation analysis of parkin,PINK1, DJ-1 and ATP13A2 gene in 30 families with AREP.In our study, mutations in the parkin,PINK1,DJ-1 and ATP13A2 genes account for up to 46.7%,6.7%,3.3%of Chinese families with AREP,respectively.The digenic inheritance of PINK1 and DJ-1 genes accounts for up to 3.3%.
2.We studied three families with the mutations of parkin、PINK1 and DJ-1 gene respectively,with a dopamine transporter ligand ~(11)C-CFT positron emission tomography(PET).A marked bilaterally and symmetrically decrement of ~(11)C-CFT uptake was found in all these patients,and putamen as well as caudate nucleus was affected.We also found asymptomatic parkin and PINK1 heteroygotes showed a mild but significant decreae in ~(11)C-CFT uptake,suggesting a sub-clinical disease process in parkin and PINK1-heterozygotes,but this phenomenon was not found in the DJ-1-heteroygotes.
3.Detailed analyse the clinic feature of the patients in the 30 families with AREP and then compare the clinic feature according to the genotype.No significant feature was found to differentiate the genotype.
DJ-1基因是常染色体隐性遗传早发性帕金森综合征(autosomalrecessive early-onset parkinsonism,AREP)的致病基因之一,目前在PD发病机制中的作用仍不清楚。前期工作中,本研究小组发现一种新的DJ-1基因突变——L10P。为探讨DJ-1基因的L10P突变在帕金森病(Parkinson's disease,PD)发病机制中的作用,我们从以下3个方面进行了研究:
1.应用G418进行稳定表达pCMV-Tag 2A-Flag、pCMV-Tag2A-Flag-DJ-1、pCMV-Tag 2A-Flag-DJ-1-L10P的HEK293单克隆细胞株的筛选,并在DNA、RNA和蛋白质三个水平上进行鉴定,证实获得稳定表达空载体、野生型DJ-1蛋白、L10P突变型DJ-1蛋白的HEK293单克隆细胞株。
2.应用流式细胞仪、分光光度计、电镜等技术对稳定表达空载体、野生型DJ-1蛋白、L10P突变型DJ-1蛋白的HEK293单克隆细胞株的生长活力、活性氧、膜电位、线粒体复合体酶Ⅰ活性及线粒体形态进行分析,结果发现与空载体组相比较,L10P突变型DJ-1组细胞内活性氧增高,细胞活力、膜电位、线粒体复合体Ⅰ活性降低,线粒体含量减少,出现线粒体肿胀,甚至线粒体空泡变性,特别是在鱼藤酮的诱导下更明显;野生型DJ-1组细胞内野生型DJ-1组中活性氧均较低,细胞活力、膜电位、线粒体复合体Ⅰ活性均较高,特别是在鱼藤酮的诱导下更明显,提示L10P突变型DJ-1蛋白存在细胞毒性作用,丧失了野生型DJ-1蛋白的抗氧化应激能力,并对线粒体的正常功能存在影响。
3.为明确L10P突变型DJ-1蛋白是否可能通过转录调控活性的变化导致相关基因表达异常而参与PD的发病机制,我们应用基因表达微珠芯片对稳定表达空载体、野生型DJ-1蛋白、L10P突变型DJ-1蛋白的HEK293单克隆细胞株进行差异表达基因筛选,结果发现与空载体组比较,野生型DJ-1组有14个基因表达上调,28个基因表达下调;L10P突变型DJ-1组有14个基因表达上调,9个基因表达下调。L10P突变型DJ-1组与野生型型DJ-1组比较发现有59个基因表达上调,27个基因表达下调。进一步分析发现这些表达差异基因分别参与信号转导、细胞粘附、基因转录调控、细胞周期、蛋白修饰、细胞凋亡、氧化应激等生物学过程,提示L10P突变型DJ-1蛋白可能通过直接或间接方式对这些差异基因进行表达调控,进而影响这些通路的正常功能,参与PD的发病机制。
第二部分常染色体隐性遗传早发性帕金森综合征基因型与表型分析
AREP有3种基因型(PARK2、PARK6和PARK7),致病基因分别是:parkin、PINK1和DJ-1基因。为探讨AREP的基因型与表型是否相关,我们从以下3个方面进行了研究:
1.建立了应用实时荧光定量PCR技术检测parkin基因外显子重排突变的技术平台和应用DNA直接测序检测ATP13A2基因突变的技术平台,完善了30个AREP家系的parkin、PINK1、DJ-1和ATP13A2基因的突变分析,结果发现在该组AREP家系中parkin、PINK1、DJ-1和ATP13A2基因的突变率分别为46.7%、6.7%、3.3%、0%,而PINK1和DJ-1双基因突变的频率为3.3%。
2.分别对一个携带parkin、PINK1、DJ-1基因突变的AREP家系进行以~(11)C-CFT标记多巴胺转运体蛋白的PET分析,发现所有的患者多巴胺转运体显像信号明显减低,与临床症状严重程度呈负相关;对家系杂合子的研究发现parkin、PINK1基因突变携带者多巴胺转运体显像信号双侧对称性减低,而DJ-1基因突变携带者多巴胺转运体显像信号双侧对称,无明显减低,提示parkin和PINK1基因的杂合子突变可能具有致病性。
3.详细分析了30个AREP家系患者的临床资料,并根据基因突变检测结果对各亚型进行临床分析,结果未发现具有明显基因型指向的临床表型。
PartⅠThe effect of mutated DJ-1 protein to cellular mitochondrial function and expression profiles of genes
DJ-1 gene is one of the pathogenic genes that are responsible for autosomal recessive early-onset parkinsonism(AREP)and its effect to the pathogenesis of Parkinson's disease(PD)is still unknown.In our prophase works,a novel DJ-1 mutation(L10P)was found.To elucidate the effect of L10P mutated DJ-1 protein to the pathogenesis of PD,we investigated the function of DJ-1 on the following three aspects:
1.To generate HEK293 monoclone cell lines which are stably expressing Flag-tagged wild-type and L10P mutated DJ-1 protein, G418(800μg/ml)was used when pCMV-Tag 2A-Flag-DJ-1、pCMV-Tag 2A-Flag-DJ-1-L10P were transfected.To confirm the HEK293 monoclone cell lines which can stably express Flag-tagged wild-type and L10P mutated DJ-1 protein,we identified the transfected plasmids were conformed in the gDNA,could be transcripted in the RNA level and expressed protein with the Flag tag.We got the HEK293 monoclone cell lines which were stably expressing empty vector,Flag-tagged wild-type and L10P mutated DJ-1 protein successfully.
2.Using spectrophotometer,flow cytometry and electron microscope to investigate cell viability,reactive oxygen species(ROS), mitochondrial transmembrane potential,complexⅠactivity and mitochondfial morphous of the HEK293 monoclone cell lines which are stably expressing wild-type and L10P mutated DJ-1 protein.Compared with the cell lines expressing empty vector,we found the ROS was increased,the cell viability,mitochondrial transmembrane potential, complexⅠactivity were reduced in these cell expressing L10P mutated DJ-1 protein.We also found mitochondria in these cells were swelling and some mitochondria were vacuolar degeneration.These phenomena were more obvious when rotenone was used.But in the cell expressing wild-type DJ-1,ROS was lower,the cell viability,mitochondrial transmembrane potential,complexⅠactivity were higher than other cell lines,especially under the induction of rotenone.It suggested that L10P mutated DJ-1 protein probably loss the ability of anti-oxidative stress and affect the normal function of mitochondria.
3.To identify genes for which expressions are abnormally regulated by L10P mutated DJ-1 protein,DNA microarray analyses were carried out using HEK293 monoclone cell lines which are stably expressing empty vector,wild-type and L10P mutated DJ-1 protein.Compared with the cell lines expressing empty vector,we found expression levels of 14 and 28 genes in expressing wild-type DJ-1 protein cells and expression levels of 14 and 9 genes in expressing L10P mutated DJ-1 protein cells increased and decreased,respectively.Compared with the cell lines expressing wild-type DJ-1 protein,we found expression levels of 59 and 27 genes in expressing L10P mutated DJ-1 protein cells increased and decreased,respectively.These genes were classified genes related to signal transduction,cell adhesion,regulation of transcription,regulation of cell cycle,protein modification,apoptosis,oxidative stress and neurotoxicity.It suggested that L10P mutated DJ-1 protein probably affects the normal function of these pathways via changing these associated gene express level to participate the pathogenesis of PD.
PartⅡThe correlation analysis of genotype and phenotype of autosomal recessive early-onset parkinsonism
Three loci,for autosomal recessive early-onset parkinsonism(AREP) have been mapped thus far(PARK2,PARK6 and PARK7)and all the three pathogenic genes have been cloned,that is parkin,PINK1 and DJ-1. To elucidate the correlation between genotype and phenotype of AREP, we investigated the following three aspects:
1.After establishing the methods of real-time PCR to screen parkin gene rearrangement and DNA direct sequencing to detect the ATP13A2 gene mutation,we consummated the mutation analysis of parkin,PINK1, DJ-1 and ATP13A2 gene in 30 families with AREP.In our study, mutations in the parkin,PINK1,DJ-1 and ATP13A2 genes account for up to 46.7%,6.7%,3.3%of Chinese families with AREP,respectively.The digenic inheritance of PINK1 and DJ-1 genes accounts for up to 3.3%.
2.We studied three families with the mutations of parkin、PINK1 and DJ-1 gene respectively,with a dopamine transporter ligand ~(11)C-CFT positron emission tomography(PET).A marked bilaterally and symmetrically decrement of ~(11)C-CFT uptake was found in all these patients,and putamen as well as caudate nucleus was affected.We also found asymptomatic parkin and PINK1 heteroygotes showed a mild but significant decreae in ~(11)C-CFT uptake,suggesting a sub-clinical disease process in parkin and PINK1-heterozygotes,but this phenomenon was not found in the DJ-1-heteroygotes.
3.Detailed analyse the clinic feature of the patients in the 30 families with AREP and then compare the clinic feature according to the genotype.No significant feature was found to differentiate the genotype.
引文
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