癫痫突触机制中发动蛋白、突触融合蛋白、突触囊泡膜蛋白及相关蛋白研究
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摘要
第一部分:耐药性癫痫患者突触囊泡相关蛋白研究
目的:在本课题组既往耐药性癫痫患者和癫痫模型脑组织基因芯片研究基础上,检测耐药性癫痫患者脑组织中突触囊泡功能相关蛋白的差异表达,探索突触囊泡功能相关蛋白在耐药性癫痫突触机制中的作用。
方法:收集耐药性癫痫患者手术后的脑组织,按病程不同分为短病程和长病程两组,采用RT-PCR、免疫组化、免疫荧光、western blot分别对突触囊泡相关蛋白Dnm1,Stx1和Syt1的表达部位和表达量进行测定,通过与对照组的比较,探讨其在耐药性癫痫发病机制中的作用。
结果:我们的结果发现Dnm1,Stx1和Syt1主要在神经元胞膜和胞浆中表达。其中,Dnm1在长病程和短病程的耐药性癫痫患者中表达较对照组显著增强(P<0.05),而在长短病程组间无显著差异(P>0.05);Stx1和Syt1在长病程的耐药性癫痫患者中表达较短病程组和对照组显著增强(P<0.05), Stx1和Syt1的表达在短病程和对照组间无显著差异(P>0.05)。
结论:研究提示耐药性癫痫患者脑组织中存在突触囊泡相关蛋白的差异表达,这些改变在耐药性癫痫的发病及维持中可能起一定作用。其中,Dnm1主要参与网格蛋白介导的突触囊泡的内吞过程,其高表达提示在癫痫患者病程早期就存在囊泡内吞功能的加强;Stx 1主要与胞吐过程中囊泡与胞膜的融合有关,Syt 1作为钙感受器调节囊泡的胞吐过程,同时也与其他蛋白协同,促进网格蛋白包被的形成,调节囊泡的内吞,所以在耐药性癫痫的后期,突触囊泡的内吞和胞吐功能均增强,提示囊泡循环的增强在耐药性癫痫的发生及发展中有重要作用。
第二部分:耐药性癫痫患者血液、脑脊液中Dnm1、talin2及κ-IgLC,λ-IgLC蛋白的检测
目的:本课题组在前期耐药性癫痫患者脑脊液蛋白质组学研究中发现,talin 2蛋白出现在癫痫患者脑脊液中,在对照组没有表达。talin 2是一种细胞粘附因子,存在于突触部位,可能与突触功能相关。基于此,我们设计了本研究,以进一步了解血液、脑脊液中突触相关蛋白Dnm 1和talin 2的差异表达和κ-IgLC,λ-IgLC的变化,为临床寻找新的药物治疗靶点和生物标记物提供实验依据。
方法:将患者分为四组:病毒性脑炎组(AE),病毒性脑炎合并癫痫发作组(AESS),治疗有效脑炎后癫痫(EPEE)及难治性脑炎后癫痫组(RPEE),分别采集血清、脑脊液。运用酶联免疫吸附试验(ELISA)定量测定血清、脑脊液中的talin2,Dnm1、κ-IgLC,λ-IgLC的浓度,并与对照组进行比较。
结果:共62例患者纳入AE组(n=16),AESS(n=16),EPEE(n=15)及RPEE(n=15)。结果发现在AE、AESS、PEE及RPEE组脑脊液中的Dnm1浓度与血清中没有显著差异;RPEE组脑脊液中talin2的表达显著高于其他组,而血清中talin2低于其他组;脑脊液中κ-IgLC,λ-IgLC和相应IgLCκ/λ比值的变化在各组中无显著差异,而血清中κ-IgLC,λ-IgLC和IgLCκ/λ比值在各组间有显著差异:在RPEE中,血清κ-IgLC浓度较其他三组显著增高;在RPEE中,血清λ-IgLC浓度较其他三组显著降低,而EPEE和AESS的血清λ-IgLC浓度较AE患者显著降低;血清IgLCκ/λ比值在RPEE中显著高于其他三组,而EPEE和AESS的血清IgLCκ/λ比值较AE患者显著增高。
结论: talin 2在RPEE患者脑脊液、血清中的表达显著增高,提示耐药性癫痫的形成可能与talin2参与的突触囊泡回收功能障碍有关;血清而非脑脊液中的κ-IgLC,λ-IgLC和相应IgLCκ/λ比值的改变,特别是RPEE中超高水平的血清IgLCκ/λ比值似乎提示其可以作为一个耐药性癫痫预后判断指标,RPEE可能是IVIg治疗的适合人群。Dnm 1在各组中无显著差异,与脑组织中的变化不同表明脑脊液和脑组织间在此方面存在组织学差异。
PART ONE: EXPRESSIONS OF SYNAPTIC VESICLE RELATED PROTEINS IN THE BRAIN TISSUE OF REFRACTORY EPILEPTIC PATIENTS
Objective Based on the previous study of gene chips in refractory patients and kindling models, we detected the expression of genes and proteins related to synaptic vesicle recycling in the brains of refractory epileptic patients, to further explore the synapse function in human intractable epilepsy.
Methods the temporal brain tissue from refractory epilepsy patients and head trauma patients were obtained. The refractory epilepsy patients were divided into two groups: the long illness duration and short illness duration groups, and the head trauma patients were used as control. RT-PCR, western blot, Immunohistochemistryand immunofluorescence were used to examine the mRNA expressions and protein expression of Dnm 1, Stx 1 and Syt 1.
Results Dnm 1, Stx 1 and Syt 1 maily confined to the cytoplasm and cytomembrane. As compared with the control group, there appeared significant increased mRNA and protein level of Dnm 1 in long and short illness duration RE patients; there was no significant difference between 2 groups of RE. As to Stx 1 and Syt 1, the expressions were significantly up-regulated in long illness duration RE patients when compared with those in short illness duration RE and control., and there were no difference between hort illness duration RE and control.
Conclusion The altered expressions of genes and proteins related to synaptic vesicle indicated that the synaptic visicle recycling was changed in the brains of RE. Dnm 1 is involved in the endocytosis of synaptic vesicle high levels of neuronal activity, our results suggested that Dyn 1 might be involved in the epileptogenesis of RE in the early stage through modulating endocytosis of neurotransmitter; Stx 1A is involved in vesicle fusion step and plays a key role in exocytosis and Syt 1 is involved in both exocytosis and endocytosis of synaptic vesicle. Our present results suggested that in the later stage of RE, both the exocytosis and endocytosis of synaptic vesicle were strengthened in refractory epileptic patients. Thus , the enhanced synaptic vesicle circulation may play an important role in the RE.
PART TWO: THE CSF AND SERUM CONCENTRATION OF DNM 1, TALIN 2,Κ-IGLC,λ-IGLC IN POSTENCEPHALITIC EPILEPSY PATIENTS
Aim: A previous proteomics study found that talin 2 presented in the cerebrospinal fluid (CSF) of epileptic patients only but not in healthy controls . Talin 2 is found in focal cell adhesion and synapse and play role at those place.
Methods: A total of 62 patients agreed to participate in the study. Dnm 1, Talin 2 were detected in the CSF and serum of and drug-effective post-encephalitic epilepsy(EPEE), drug-refractory post-encephalitic epilepsy( PEE), acute encephalitis with secondary seizures (AESS) acute encephalitis without secondary seizures (AE) patients using sandwich enzyme-linked immunosorbent assays.
Results: A total of 62 patients agreed to participate in the study. The Dnm 1 concentrations of CSF and serum in AE, AESS,EPSS and RPEE had no significant difference(P>0.05);RPEE CSF talin 2 concentrations were greater when compared to AE, EPEE and AESS (p <0.05), While the serum talin 2 concentrations were significantly decreased in RPEE when compared with other 3 groups(p <0.05); the changes in CSFκ-IgLC,λ-IgLC and IgLCκ/λratio had no statistical difference among RPEE, EPEE, AESS and AE groups, but the changes in serumκ-IgLC,λ-IgLC and IgLCκ/λratio had extraordinary statistical difference: the serumκ-IgLC concentrations were significantly increased in RPEE; The serumλ-IgLC is significantly lower in RPEE when compared with other 3 groups and the concentrations in EPEE and AESS were significantly lower than that in AE; The serum IgLCκ/λratios in RPEE was significantly higher than other 3 groups and the ratios in EPEE and AESS were significantly higher than that in AE.
Conclusions: We suggest that the differential concentration of CSF and serum talin 2 in RPEE is an intractability-related phenomenon but not a seizure-related phenomenon. The striking change of serumλ-IgLC andΚ/λratio in RPEE might be used as a diagnostic or prognostic parameter for RPEE and RPEE patients might be a target for immunoglobulin therapy.
目的:在本课题组既往耐药性癫痫患者和癫痫模型脑组织基因芯片研究基础上,检测耐药性癫痫患者脑组织中突触囊泡功能相关蛋白的差异表达,探索突触囊泡功能相关蛋白在耐药性癫痫突触机制中的作用。
方法:收集耐药性癫痫患者手术后的脑组织,按病程不同分为短病程和长病程两组,采用RT-PCR、免疫组化、免疫荧光、western blot分别对突触囊泡相关蛋白Dnm1,Stx1和Syt1的表达部位和表达量进行测定,通过与对照组的比较,探讨其在耐药性癫痫发病机制中的作用。
结果:我们的结果发现Dnm1,Stx1和Syt1主要在神经元胞膜和胞浆中表达。其中,Dnm1在长病程和短病程的耐药性癫痫患者中表达较对照组显著增强(P<0.05),而在长短病程组间无显著差异(P>0.05);Stx1和Syt1在长病程的耐药性癫痫患者中表达较短病程组和对照组显著增强(P<0.05), Stx1和Syt1的表达在短病程和对照组间无显著差异(P>0.05)。
结论:研究提示耐药性癫痫患者脑组织中存在突触囊泡相关蛋白的差异表达,这些改变在耐药性癫痫的发病及维持中可能起一定作用。其中,Dnm1主要参与网格蛋白介导的突触囊泡的内吞过程,其高表达提示在癫痫患者病程早期就存在囊泡内吞功能的加强;Stx 1主要与胞吐过程中囊泡与胞膜的融合有关,Syt 1作为钙感受器调节囊泡的胞吐过程,同时也与其他蛋白协同,促进网格蛋白包被的形成,调节囊泡的内吞,所以在耐药性癫痫的后期,突触囊泡的内吞和胞吐功能均增强,提示囊泡循环的增强在耐药性癫痫的发生及发展中有重要作用。
第二部分:耐药性癫痫患者血液、脑脊液中Dnm1、talin2及κ-IgLC,λ-IgLC蛋白的检测
目的:本课题组在前期耐药性癫痫患者脑脊液蛋白质组学研究中发现,talin 2蛋白出现在癫痫患者脑脊液中,在对照组没有表达。talin 2是一种细胞粘附因子,存在于突触部位,可能与突触功能相关。基于此,我们设计了本研究,以进一步了解血液、脑脊液中突触相关蛋白Dnm 1和talin 2的差异表达和κ-IgLC,λ-IgLC的变化,为临床寻找新的药物治疗靶点和生物标记物提供实验依据。
方法:将患者分为四组:病毒性脑炎组(AE),病毒性脑炎合并癫痫发作组(AESS),治疗有效脑炎后癫痫(EPEE)及难治性脑炎后癫痫组(RPEE),分别采集血清、脑脊液。运用酶联免疫吸附试验(ELISA)定量测定血清、脑脊液中的talin2,Dnm1、κ-IgLC,λ-IgLC的浓度,并与对照组进行比较。
结果:共62例患者纳入AE组(n=16),AESS(n=16),EPEE(n=15)及RPEE(n=15)。结果发现在AE、AESS、PEE及RPEE组脑脊液中的Dnm1浓度与血清中没有显著差异;RPEE组脑脊液中talin2的表达显著高于其他组,而血清中talin2低于其他组;脑脊液中κ-IgLC,λ-IgLC和相应IgLCκ/λ比值的变化在各组中无显著差异,而血清中κ-IgLC,λ-IgLC和IgLCκ/λ比值在各组间有显著差异:在RPEE中,血清κ-IgLC浓度较其他三组显著增高;在RPEE中,血清λ-IgLC浓度较其他三组显著降低,而EPEE和AESS的血清λ-IgLC浓度较AE患者显著降低;血清IgLCκ/λ比值在RPEE中显著高于其他三组,而EPEE和AESS的血清IgLCκ/λ比值较AE患者显著增高。
结论: talin 2在RPEE患者脑脊液、血清中的表达显著增高,提示耐药性癫痫的形成可能与talin2参与的突触囊泡回收功能障碍有关;血清而非脑脊液中的κ-IgLC,λ-IgLC和相应IgLCκ/λ比值的改变,特别是RPEE中超高水平的血清IgLCκ/λ比值似乎提示其可以作为一个耐药性癫痫预后判断指标,RPEE可能是IVIg治疗的适合人群。Dnm 1在各组中无显著差异,与脑组织中的变化不同表明脑脊液和脑组织间在此方面存在组织学差异。
PART ONE: EXPRESSIONS OF SYNAPTIC VESICLE RELATED PROTEINS IN THE BRAIN TISSUE OF REFRACTORY EPILEPTIC PATIENTS
Objective Based on the previous study of gene chips in refractory patients and kindling models, we detected the expression of genes and proteins related to synaptic vesicle recycling in the brains of refractory epileptic patients, to further explore the synapse function in human intractable epilepsy.
Methods the temporal brain tissue from refractory epilepsy patients and head trauma patients were obtained. The refractory epilepsy patients were divided into two groups: the long illness duration and short illness duration groups, and the head trauma patients were used as control. RT-PCR, western blot, Immunohistochemistryand immunofluorescence were used to examine the mRNA expressions and protein expression of Dnm 1, Stx 1 and Syt 1.
Results Dnm 1, Stx 1 and Syt 1 maily confined to the cytoplasm and cytomembrane. As compared with the control group, there appeared significant increased mRNA and protein level of Dnm 1 in long and short illness duration RE patients; there was no significant difference between 2 groups of RE. As to Stx 1 and Syt 1, the expressions were significantly up-regulated in long illness duration RE patients when compared with those in short illness duration RE and control., and there were no difference between hort illness duration RE and control.
Conclusion The altered expressions of genes and proteins related to synaptic vesicle indicated that the synaptic visicle recycling was changed in the brains of RE. Dnm 1 is involved in the endocytosis of synaptic vesicle high levels of neuronal activity, our results suggested that Dyn 1 might be involved in the epileptogenesis of RE in the early stage through modulating endocytosis of neurotransmitter; Stx 1A is involved in vesicle fusion step and plays a key role in exocytosis and Syt 1 is involved in both exocytosis and endocytosis of synaptic vesicle. Our present results suggested that in the later stage of RE, both the exocytosis and endocytosis of synaptic vesicle were strengthened in refractory epileptic patients. Thus , the enhanced synaptic vesicle circulation may play an important role in the RE.
PART TWO: THE CSF AND SERUM CONCENTRATION OF DNM 1, TALIN 2,Κ-IGLC,λ-IGLC IN POSTENCEPHALITIC EPILEPSY PATIENTS
Aim: A previous proteomics study found that talin 2 presented in the cerebrospinal fluid (CSF) of epileptic patients only but not in healthy controls . Talin 2 is found in focal cell adhesion and synapse and play role at those place.
Methods: A total of 62 patients agreed to participate in the study. Dnm 1, Talin 2 were detected in the CSF and serum of and drug-effective post-encephalitic epilepsy(EPEE), drug-refractory post-encephalitic epilepsy( PEE), acute encephalitis with secondary seizures (AESS) acute encephalitis without secondary seizures (AE) patients using sandwich enzyme-linked immunosorbent assays.
Results: A total of 62 patients agreed to participate in the study. The Dnm 1 concentrations of CSF and serum in AE, AESS,EPSS and RPEE had no significant difference(P>0.05);RPEE CSF talin 2 concentrations were greater when compared to AE, EPEE and AESS (p <0.05), While the serum talin 2 concentrations were significantly decreased in RPEE when compared with other 3 groups(p <0.05); the changes in CSFκ-IgLC,λ-IgLC and IgLCκ/λratio had no statistical difference among RPEE, EPEE, AESS and AE groups, but the changes in serumκ-IgLC,λ-IgLC and IgLCκ/λratio had extraordinary statistical difference: the serumκ-IgLC concentrations were significantly increased in RPEE; The serumλ-IgLC is significantly lower in RPEE when compared with other 3 groups and the concentrations in EPEE and AESS were significantly lower than that in AE; The serum IgLCκ/λratios in RPEE was significantly higher than other 3 groups and the ratios in EPEE and AESS were significantly higher than that in AE.
Conclusions: We suggest that the differential concentration of CSF and serum talin 2 in RPEE is an intractability-related phenomenon but not a seizure-related phenomenon. The striking change of serumλ-IgLC andΚ/λratio in RPEE might be used as a diagnostic or prognostic parameter for RPEE and RPEE patients might be a target for immunoglobulin therapy.
引文
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