神经蛋白tau在Scrapie动物模型和CJD病人组织中变化的研究
摘要
可传播性海绵状脑病(Transmissible spongiform encephalopathies,TSEs)也称为朊病毒病(prion diseases),是一类可感染人类和多种动物罕见的致死性的神经系统退行性疾病,包括人类的克雅氏病(Creutzfeldt-Jakob disease,CJD)、GSS综合症(Gerstmann—Str(a|¨)ussler-Scheinker syndrome,GSS)、Kuru病、家族性致死性失眠症(fatal familial insomnia,FFI),以及动物的羊瘙痒病(Scrapie)、牛海绵状脑病(bovine spongiform encephalopathy,BSE)和鹿的慢性消耗性疾病(chronic wasting disease,CWD)等,根据疾病的来源不同可分为自发形成、遗传性和医源性三种形式。本文分为两部分,第一部分我们分别采用Western blot和real-time PCR方法检测了感染羊瘙痒因子的仓鼠脑组织中tau蛋白、磷酸化tau蛋白和蛋白激酶在表达和转录水平上的变化,以揭示这些生物活性蛋白与TSE发病机制之间的潜在联系。第二部分我们采用Western blot方法检测了202份疑似CJD病人脑脊液(cerebrospinal fluid,CSF)样品中14-3-3蛋白的阳性/阴性,以ELISA法测定了CSF中tau蛋白的浓度,分析CSF中14-3-3蛋白与tau蛋白的相关性以及这两种蛋白与病人主要临床症状之间的相关性,以评价CSF中tau蛋白在诊断CJD上的敏感性和特异性。
第一部分:感染Scrapie仓鼠脑组织中tau蛋白与蛋白激酶关系的研究
首先我们应用Western blot方法检测了感染羊瘙痒因子263K或139A终末期的仓鼠脑组织中是否含有PrP~(Sc),结果表明在所有感染发病的动物脑组织中均检测到了PrP~(Sc)。
在GSS中tau蛋白的磷酸化水平升高而在sCJD中tau蛋白的磷酸化水平未发生改变,为了检测感染Scrapie的仓鼠脑组织中tau蛋白和磷酸化tau蛋白在表达水平上的变化,我们利用Western blot方法检测了感染羊瘙痒因子263K或139A终末期的仓鼠脑组织中tau蛋白、p-tau(Ser396)、p-tau(Ser404)和p-tau(Ser202/Thr205)的含量。结果表明与正常对照相比,感染Scrapie终末期的仓鼠脑组织中p-tau(Ser396)和p-tau(Ser404)的水平显著降低而p-tau(Ser202/Thr205)的水平显著升高。此外我们通过real-time PCR检测了tau在转录水平上的变化。结果表明在感染Scrapie的仓鼠脑组织中Tau4的转录水平显著升高而Tau2的转录水平仅稍有升高。这些结果提示在感染Scrapie的仓鼠脑组织中tau、p-tau(Ser396)、p-tau(Ser404)和p-tau(Ser202/Thr205)水平的改变可能是与TSE相关的,并且该现象与羊瘙痒因子的毒株和潜伏期无关。
由于GSK3β和CDK5在tau蛋白的磷酸化过程中起着重要作用,我们通过Western blot和real-time PCR方法分别检测了感染Scrapie的仓鼠脑组织中这两种蛋白激酶的表达和转录水平。Western blot结果表明感染羊瘙痒因子263K或139A终末期的仓鼠脑组织中GSK3β含量降低而CDK5的含量升高;real-time PCR也显示相似的结果即GSK3β的转录水平显著降低而CDK5的转录水平显著升高。
为了研究感染Scrapie的仓鼠在潜伏期中tau、p-tau(Ser396)、p-tau(Ser404)、p-tau(Ser202/Thr205)、GSK3β和CDK5含量的变化趋势,我们通过Western blot和real-time PCR分别检测了颅内接种羊瘙痒因子263K后第20天、40天、50天、60天和70天所取仓鼠脑组织中上述生物因子的表达和转录水平。结果显示在潜伏期中感染Scrapie的仓鼠脑组织中tau、p-tau(Ser202/Thr205)和CDK5的信号逐渐增强,而p-tau(Ser396)、p-tau(Ser404)和GSK3β的信号逐渐减弱,这些生物活性蛋白的变化是呈时间相关性的,并且远远早于临床症状的出现。在潜伏期内GSK3β水平逐渐降低正好与p-tau(Ser396)和p-tau(Ser404)的降低一致,而CDK5水平逐渐升高恰好与p-tau(Ser202/Thr205)的升高相一致。这种现象可能表明p-tau(Ser202/Thr205)水平的升高是由CDK5的变化引起的;而p-tau(Ser396)和p-tau(Ser404)的水平降低则是由GSK3β引起的。
在感染Scrapie的仓鼠脑组织中PrP~(Sc)、tau蛋白、磷酸化tau蛋白和蛋白激酶等的变化构成了一个复杂的网络。尽管目前还不清楚它们是在何时以何种方式发挥作用并互相影响,除了PrP~(Sc)的沉积作为始动因素外,这些生物活性蛋白的变化在TSE的发病机制中或者起着媒介作用或者是由疾病而引发的结果。提示这些生物活性蛋白可能与Scrapie的发病机制有潜在的联系,详细研究这些生物活性蛋白在感染Scrapie动物神经组织中的变化能够有助于阐明该病的致病机制。
第二部分:中国临床诊断克雅氏病人脑脊液中tau蛋白浓度诊断价值的研究
为了研究CSF中tau蛋白在诊断CJD上的敏感性和特异性,以及是否亚洲散发型CJD病人与其他种族病人一样CSF中tau蛋白也升高。我们通过Westernblot检测了202份CSF样品中14-3-3蛋白的阳性/阴性,其中40份来自临床诊断CJD病人,27份来自疑似诊断CJD病人,135份来自非CJD病人;采用Innogenetic公司的ELISA试剂盒测定了CSF中tau蛋白的浓度,并评价了CSF中tau蛋白在辅助诊断中国临床诊断CJD中的作用;所有病人的PRNP基因均送测序,以确定PRNP基因129位多态性,并排除fCJD。结果显示与疑似诊断CJD病人和对照相比,CSF中14-3-3蛋白的阳性率和tau蛋白浓度在临床诊断CJD病人(p＜0.001)中显著升高。用于诊断临床诊断CJD病人时,CSF中tau蛋白浓度以大于1400 pg/ml为临界值,其特异性为94%,敏感性为90%。联合应用14-3-3和tau蛋白后特异性升高而敏感性稍有下降。该结果提示检测CSF中tau蛋白的浓度有助于CJD的诊断。
为了研究CSF中tau蛋白浓度与病人年龄、性别、CSF取样时间、典型脑电图、典型核磁共振、129位多态性、CSF中14-3-3蛋白和病人主要临床症状之间的相关性,将病人按照发病年龄、性别、CSF取样时间、脑电图是否典型、核磁共振是否典型、129位多态性、CSF中14-3-3蛋白阳性/阴性和主要临床症状分为不同的组别,分别做统计学分析。统计结果显示CSF中tau蛋白浓度与病人年龄、性别、CSF取样时间、典型脑电图、典型核磁共振、129位多态性和病人主要临床症状之间均无相关性,而CSF中tau蛋白浓度与14-3-3阳性具有极高的相关性。CSF中14-3-3蛋白已被WHO列入了CJD的诊断标准,所以表明CSF中tau蛋白的浓度有助于CJD的诊断。
Transmissible spongiform encephalopathies(TSEs),prion diseases,are rare degenerative neurological disorders that afflict human beings,including Creutzfeldt-Jakob disease(CJD),Gerstmann-Str(a|¨)ussler-Scheinker syndrome(GSS),Kuru,and fatal familial insomnia(FFI),sheep and goat(scrapie),cattle(bovine spongiform encephalopathy,BSE), and other animals.They may have a sporadic,inherited or acquired origin.This study contains two individual parts,including analysis of the relation of changes of tau profiles in brains of the hamsters infected with scrapie strains 263K or 139A with the alteration of phosphate kinases,and the study of the tau level in CSF of Chinese patients with probable diagnostic Creutzfeldt-Jakob disease.
PartⅠ:Changes of tau profiles in brains of the hamsters infected with scrapie strains 263K or 139A possibly associated with the alteration of phosphate kinases
To investigate the possible changes of tau in scrapie experimental animals,the profiles of tau and phosphorylated tau(p-tau,at Ser396,Ser404,and Ser202/Thr205) in the brain tissues of agents 263K- or 139A-infected hamsters were evaluated by Western blots.The result showed that the contents of total tau and p-tau at Ser202/Thr205 increased,but p-tau at Ser396 and Ser404 decreased at the terminal stages.To assess the transcription of tau mRNA in brains,real time-PCR reactions were performed.The assays revealed that the level of Tau-4 transcript was remarkably increased and that of Tau-2 transcript was slightly increased in the brain tissues of scrapie-infected hamsters.These results highlight that the transcriptional and expressive changes of tau profiles are a common phenomenon of scrapie experimental animals,neither related with scrapie strains nor incubation periods.
Both GSK3βand CDK5 played an important role in mediating tau phosphorylation,the expressive and transcriptional levels of these two kinases in the brains of normal and scrapie-infected hamsters were evaluated by Western blot and real-time PCR.It showed higher CDK5,but lower GSK3βtranscriptional and expressive levels in the brains of scrapie-infected animals.
In order to investigate the dynamic changes of tau,p-tau(Ser396),p-tau(Ser404), p-tau(Ser202/Thr205),GSK3βand CDK5 in the brains of scrapie-infected hamsters during incubation period,the expressive and transcriptional levels of these biomarkers were evaluated by Western blots and real-time PCR,respectively.Brain samples of the agent 263K-infected hamsters at the 20~(th),40~(th),50~(th),60~(th) and 70~(th) days after inoculation were collected.The results showed that the signals of tau,p-tau (Ser202/Thr205),and CDK5 became stronger and that of p-tau(Ser396),p-tau (Ser404) and GSK3βbecame weaker in the infected specimens compared with the normal controls.These results indicate that changes of tau profiles and phosphate kinases happen much earlier than the onset of the clinical manifestations,showing a time-relative pattern.Moreover,gradually declined GSK3βand raised CDK5 levels correspond well with the decrease of p-tau(Ser396 and Ser404) and increase of p-tau (Ser202/Thr205),respectively.These phenomena may highlight the possibility that the increase of p-tau(Ser202/Thr205) is due to the higher level of CDK5 and depression of p-tau(Ser396 and Ser404) owes to the lower level of GSK3β.
Alterations of PrP~(Sc),tau,p-tau and kinases in the brains of TSE animals during pathogenicity may consist of a complicate network.It is still unclear when and how these components function and impact each other.Except for the deposits of PrP~(Sc) as the initiative agent,alterations of these bioactive proteins are either intermediate or consequent events in TSE pathogenesiscity and proposed the potential linkage of these bioactive proteins with the pathogenesis of prion diseases.
PartⅡ:Raised levels of tau protein in CSF of Chinese patients with probable diagnostic Creutzfeldt-Jakob disease
In order to investigate the diagnostic sensitivity and specificity of tau protein in cerebrospinal fluid(CSF) for Chinese patients with sporadic Creutzfeldt-Jakob disease (sCJD) and whether increased concentration of tau protein in CSF is the common feature for all racial CJD,especially Asian patients,total 202 CSF samples from clinically suspected sCJD patients were analyzed for the levels of tau protein with ELISA and the presences of 14-3-3 protein by immunoblot.Among them,40 were classified as probable CJD,27 as possible CJD and 135 as others.Results showed that remarkably higher values of tau protein and positive rates of 14-3-3 were observed in probable CJD,compared with possible CJD and others(p＜0.001).Using a threshold of 1400 pg/ml,tau determination showed a sensitivity of 90%and a specificity of 94%for diagnosis of probable CJD. Combining use of raised tau and positive 14-3-3 increased the specificity,but slightly reduced sensitivity.It indicated that measurement of CSF tau will be helpful for CJD diagnosis antemortem.
The relationship between the raised CSF tau and the main clinical data in the patients were analyzed.The patients were grounped according to the onset age,gender,sampling time,appearance of typical EEG,appearance of typical MRI,presentence of 14-3-3,codon 129 genotype of PRNP and appearance of the major neurological symptoms.Statistic analyses indicated that the raised tau did not correlate with main clinical characteristics,e.g. age,gender,clinical manifestations,sampling time,typical EEG and typical MRI but positive correlate with the presence of 14-3-3 in CSF.
第一部分:感染Scrapie仓鼠脑组织中tau蛋白与蛋白激酶关系的研究
首先我们应用Western blot方法检测了感染羊瘙痒因子263K或139A终末期的仓鼠脑组织中是否含有PrP~(Sc),结果表明在所有感染发病的动物脑组织中均检测到了PrP~(Sc)。
在GSS中tau蛋白的磷酸化水平升高而在sCJD中tau蛋白的磷酸化水平未发生改变,为了检测感染Scrapie的仓鼠脑组织中tau蛋白和磷酸化tau蛋白在表达水平上的变化,我们利用Western blot方法检测了感染羊瘙痒因子263K或139A终末期的仓鼠脑组织中tau蛋白、p-tau(Ser396)、p-tau(Ser404)和p-tau(Ser202/Thr205)的含量。结果表明与正常对照相比,感染Scrapie终末期的仓鼠脑组织中p-tau(Ser396)和p-tau(Ser404)的水平显著降低而p-tau(Ser202/Thr205)的水平显著升高。此外我们通过real-time PCR检测了tau在转录水平上的变化。结果表明在感染Scrapie的仓鼠脑组织中Tau4的转录水平显著升高而Tau2的转录水平仅稍有升高。这些结果提示在感染Scrapie的仓鼠脑组织中tau、p-tau(Ser396)、p-tau(Ser404)和p-tau(Ser202/Thr205)水平的改变可能是与TSE相关的,并且该现象与羊瘙痒因子的毒株和潜伏期无关。
由于GSK3β和CDK5在tau蛋白的磷酸化过程中起着重要作用,我们通过Western blot和real-time PCR方法分别检测了感染Scrapie的仓鼠脑组织中这两种蛋白激酶的表达和转录水平。Western blot结果表明感染羊瘙痒因子263K或139A终末期的仓鼠脑组织中GSK3β含量降低而CDK5的含量升高;real-time PCR也显示相似的结果即GSK3β的转录水平显著降低而CDK5的转录水平显著升高。
为了研究感染Scrapie的仓鼠在潜伏期中tau、p-tau(Ser396)、p-tau(Ser404)、p-tau(Ser202/Thr205)、GSK3β和CDK5含量的变化趋势,我们通过Western blot和real-time PCR分别检测了颅内接种羊瘙痒因子263K后第20天、40天、50天、60天和70天所取仓鼠脑组织中上述生物因子的表达和转录水平。结果显示在潜伏期中感染Scrapie的仓鼠脑组织中tau、p-tau(Ser202/Thr205)和CDK5的信号逐渐增强,而p-tau(Ser396)、p-tau(Ser404)和GSK3β的信号逐渐减弱,这些生物活性蛋白的变化是呈时间相关性的,并且远远早于临床症状的出现。在潜伏期内GSK3β水平逐渐降低正好与p-tau(Ser396)和p-tau(Ser404)的降低一致,而CDK5水平逐渐升高恰好与p-tau(Ser202/Thr205)的升高相一致。这种现象可能表明p-tau(Ser202/Thr205)水平的升高是由CDK5的变化引起的;而p-tau(Ser396)和p-tau(Ser404)的水平降低则是由GSK3β引起的。
在感染Scrapie的仓鼠脑组织中PrP~(Sc)、tau蛋白、磷酸化tau蛋白和蛋白激酶等的变化构成了一个复杂的网络。尽管目前还不清楚它们是在何时以何种方式发挥作用并互相影响,除了PrP~(Sc)的沉积作为始动因素外,这些生物活性蛋白的变化在TSE的发病机制中或者起着媒介作用或者是由疾病而引发的结果。提示这些生物活性蛋白可能与Scrapie的发病机制有潜在的联系,详细研究这些生物活性蛋白在感染Scrapie动物神经组织中的变化能够有助于阐明该病的致病机制。
第二部分:中国临床诊断克雅氏病人脑脊液中tau蛋白浓度诊断价值的研究
为了研究CSF中tau蛋白在诊断CJD上的敏感性和特异性,以及是否亚洲散发型CJD病人与其他种族病人一样CSF中tau蛋白也升高。我们通过Westernblot检测了202份CSF样品中14-3-3蛋白的阳性/阴性,其中40份来自临床诊断CJD病人,27份来自疑似诊断CJD病人,135份来自非CJD病人;采用Innogenetic公司的ELISA试剂盒测定了CSF中tau蛋白的浓度,并评价了CSF中tau蛋白在辅助诊断中国临床诊断CJD中的作用;所有病人的PRNP基因均送测序,以确定PRNP基因129位多态性,并排除fCJD。结果显示与疑似诊断CJD病人和对照相比,CSF中14-3-3蛋白的阳性率和tau蛋白浓度在临床诊断CJD病人(p＜0.001)中显著升高。用于诊断临床诊断CJD病人时,CSF中tau蛋白浓度以大于1400 pg/ml为临界值,其特异性为94%,敏感性为90%。联合应用14-3-3和tau蛋白后特异性升高而敏感性稍有下降。该结果提示检测CSF中tau蛋白的浓度有助于CJD的诊断。
为了研究CSF中tau蛋白浓度与病人年龄、性别、CSF取样时间、典型脑电图、典型核磁共振、129位多态性、CSF中14-3-3蛋白和病人主要临床症状之间的相关性,将病人按照发病年龄、性别、CSF取样时间、脑电图是否典型、核磁共振是否典型、129位多态性、CSF中14-3-3蛋白阳性/阴性和主要临床症状分为不同的组别,分别做统计学分析。统计结果显示CSF中tau蛋白浓度与病人年龄、性别、CSF取样时间、典型脑电图、典型核磁共振、129位多态性和病人主要临床症状之间均无相关性,而CSF中tau蛋白浓度与14-3-3阳性具有极高的相关性。CSF中14-3-3蛋白已被WHO列入了CJD的诊断标准,所以表明CSF中tau蛋白的浓度有助于CJD的诊断。
Transmissible spongiform encephalopathies(TSEs),prion diseases,are rare degenerative neurological disorders that afflict human beings,including Creutzfeldt-Jakob disease(CJD),Gerstmann-Str(a|¨)ussler-Scheinker syndrome(GSS),Kuru,and fatal familial insomnia(FFI),sheep and goat(scrapie),cattle(bovine spongiform encephalopathy,BSE), and other animals.They may have a sporadic,inherited or acquired origin.This study contains two individual parts,including analysis of the relation of changes of tau profiles in brains of the hamsters infected with scrapie strains 263K or 139A with the alteration of phosphate kinases,and the study of the tau level in CSF of Chinese patients with probable diagnostic Creutzfeldt-Jakob disease.
PartⅠ:Changes of tau profiles in brains of the hamsters infected with scrapie strains 263K or 139A possibly associated with the alteration of phosphate kinases
To investigate the possible changes of tau in scrapie experimental animals,the profiles of tau and phosphorylated tau(p-tau,at Ser396,Ser404,and Ser202/Thr205) in the brain tissues of agents 263K- or 139A-infected hamsters were evaluated by Western blots.The result showed that the contents of total tau and p-tau at Ser202/Thr205 increased,but p-tau at Ser396 and Ser404 decreased at the terminal stages.To assess the transcription of tau mRNA in brains,real time-PCR reactions were performed.The assays revealed that the level of Tau-4 transcript was remarkably increased and that of Tau-2 transcript was slightly increased in the brain tissues of scrapie-infected hamsters.These results highlight that the transcriptional and expressive changes of tau profiles are a common phenomenon of scrapie experimental animals,neither related with scrapie strains nor incubation periods.
Both GSK3βand CDK5 played an important role in mediating tau phosphorylation,the expressive and transcriptional levels of these two kinases in the brains of normal and scrapie-infected hamsters were evaluated by Western blot and real-time PCR.It showed higher CDK5,but lower GSK3βtranscriptional and expressive levels in the brains of scrapie-infected animals.
In order to investigate the dynamic changes of tau,p-tau(Ser396),p-tau(Ser404), p-tau(Ser202/Thr205),GSK3βand CDK5 in the brains of scrapie-infected hamsters during incubation period,the expressive and transcriptional levels of these biomarkers were evaluated by Western blots and real-time PCR,respectively.Brain samples of the agent 263K-infected hamsters at the 20~(th),40~(th),50~(th),60~(th) and 70~(th) days after inoculation were collected.The results showed that the signals of tau,p-tau (Ser202/Thr205),and CDK5 became stronger and that of p-tau(Ser396),p-tau (Ser404) and GSK3βbecame weaker in the infected specimens compared with the normal controls.These results indicate that changes of tau profiles and phosphate kinases happen much earlier than the onset of the clinical manifestations,showing a time-relative pattern.Moreover,gradually declined GSK3βand raised CDK5 levels correspond well with the decrease of p-tau(Ser396 and Ser404) and increase of p-tau (Ser202/Thr205),respectively.These phenomena may highlight the possibility that the increase of p-tau(Ser202/Thr205) is due to the higher level of CDK5 and depression of p-tau(Ser396 and Ser404) owes to the lower level of GSK3β.
Alterations of PrP~(Sc),tau,p-tau and kinases in the brains of TSE animals during pathogenicity may consist of a complicate network.It is still unclear when and how these components function and impact each other.Except for the deposits of PrP~(Sc) as the initiative agent,alterations of these bioactive proteins are either intermediate or consequent events in TSE pathogenesiscity and proposed the potential linkage of these bioactive proteins with the pathogenesis of prion diseases.
PartⅡ:Raised levels of tau protein in CSF of Chinese patients with probable diagnostic Creutzfeldt-Jakob disease
In order to investigate the diagnostic sensitivity and specificity of tau protein in cerebrospinal fluid(CSF) for Chinese patients with sporadic Creutzfeldt-Jakob disease (sCJD) and whether increased concentration of tau protein in CSF is the common feature for all racial CJD,especially Asian patients,total 202 CSF samples from clinically suspected sCJD patients were analyzed for the levels of tau protein with ELISA and the presences of 14-3-3 protein by immunoblot.Among them,40 were classified as probable CJD,27 as possible CJD and 135 as others.Results showed that remarkably higher values of tau protein and positive rates of 14-3-3 were observed in probable CJD,compared with possible CJD and others(p＜0.001).Using a threshold of 1400 pg/ml,tau determination showed a sensitivity of 90%and a specificity of 94%for diagnosis of probable CJD. Combining use of raised tau and positive 14-3-3 increased the specificity,but slightly reduced sensitivity.It indicated that measurement of CSF tau will be helpful for CJD diagnosis antemortem.
The relationship between the raised CSF tau and the main clinical data in the patients were analyzed.The patients were grounped according to the onset age,gender,sampling time,appearance of typical EEG,appearance of typical MRI,presentence of 14-3-3,codon 129 genotype of PRNP and appearance of the major neurological symptoms.Statistic analyses indicated that the raised tau did not correlate with main clinical characteristics,e.g. age,gender,clinical manifestations,sampling time,typical EEG and typical MRI but positive correlate with the presence of 14-3-3 in CSF.
引文
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