p75NTR、sortilin在黑质多巴胺能神经元的表达及其参与细胞变性的病理作用研究
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摘要
研究目的
帕金森(Parkinson’s disease,PD)是以黑质多巴胺能神经元大量变性死亡为特征的严重神经退行性疾病,其神经元变性死亡的发生原因与病理机制,仍然是制约PD临床治疗的关键问题。研究表明p75神经营养素受体(p75 neurotrophin receptor, p75NTR)是肿瘤坏死因子受体家族的重要成员,以低亲和力与神经营养素(neurotrophins,NTs)结合,介导神经元存活、分化与髓鞘形成。近来发现NT前体分子如神经生长因子前体(pro-nerve growth factor, proNGF)能够以高亲和力结合p75NTR,并通过辅助受体sortilin的协助启动细胞凋亡,在脑发育和脑损伤神经元的凋亡中发挥重要作用。成年后p75NTR主要在某些病理状态下表达,如脊髓侧索硬化症(ALS)和阿尔茨海默病(AD)等,异常表达的p75NTR参与疾病过程中的神经元变性或细胞凋亡。
但目前p75NTR与PD病理关系问题,仍是研究空白,本研究针对这一问题,探讨p75NTR与辅助受体sortilin在黑质的表达、细胞定位、KA损伤模型的动态变化、及其参与中脑黑质多巴胺能神经元变性死亡的病理作用,为揭示p75NTR、sortilin凋亡信号参与PD病理发展机制和疾病治疗新靶点提供依据。
研究方法
①采用红藻氨酸(kainic acid,KA)立体定位注射黑质建立兴奋性毒性损伤动物模型。
②通过半定量聚合酶链式反应(RT-PCR)检测p75NTR、sortilin、proNGFmRNA在黑质表达及其损伤后的变化。
③免疫细胞化学、双标记、及激光共聚焦显微镜观察等方法,研究p75NTR、sortilin、proNGF在黑质多巴胺能神经元的定位。
④Western Blot分析p75NTR、sortilin、proNGF蛋白在黑质的表达情况与水平变化。
⑤F luoro-Jade C(FJC)染色方法显示和计数分析黑质神经元变性死亡。
⑥细胞内凋亡信号的分析初步观察JNK、AIF细胞内信号通路的参与问题。
主要结果
1.发现p75NTR、sortilin在黑质多巴胺能神经元的表达,KA损伤后导致其表达上调。
①免疫细胞化学研究发现黑质p75NTR和sortilin的表达:在中脑黑质切片上,检测到p75NTR、sortilin阳性神经元,它们主要分布在黑质的致密部。双标记染色与激光共聚焦显微镜观察证明47%TH阳性神经元表达p75NTR,而sortilin表达于全部的TH阳性神经元。
②RT-PCR实验证明黑质p75NTR、sortilin mRNA的表达:RT-PCR结果发现p75NTR、sortilin mRNA阳性条带,p75NTR条带大小为309bp,sortilin条带大小为438bp,与预期的结果相符。
③KA损伤导致黑质p75NTR、sortilin表达上调: p75NTR mRNA相对光密度由正常黑质的0.489±0.079上升为1.06±0.11(p﹤0.01,t test);sortilin mRNA相对光密度由正常黑质的0.724±0.056上升为1.226±0.078(p﹤0.01,t test);KA损伤后p75NTR上调表达于所有的TH免疫阳性神经元,sortilin的细胞数由204±4上升到293±13,具有统计学差异(p﹤0.01)。
2.p75NTR、sortilin表达上调参与KA损伤模型黑质多巴胺能神经元变性死亡
①p 75NTR、sortilin共存于黑质多巴胺能神经元:在p75NTR/TH、sortilin/TH双标结果基础上,进一步观察到大量的p75NTR/sortilin双标记神经元分布在黑质致密部,这些双标记神经元占全部p75NTR神经元的71.8%。
②proNGF免疫阳性存在黑质神经元及星形胶质细胞:免疫细胞化学结果显示proNGF定位于黑质致密部腹侧带的多巴胺神经元,并且发现proNGF定位于激活的星形胶质细胞。
③p roNGF在KA损伤后呈现与p75NTR、sortilin共同上调现象: proNGF mRNA相对光密度由正常黑质0.18±0.037上升为0.703±0.059(p﹤0.01,t test); proNGF/TH双标细胞数由正常黑质40±5,增加到75±5,具有统计学差异(p﹤0.01)。
④p 75NTR、sortilin、proNGF、FJC及TH阳性细胞在KA损伤后的d1、d3、d7天时的动态变化:细胞计数结果显示p75NTR、sortilin、proNGF逐渐增加,TH神经元逐渐减少,同时FJC标记的变性神经元逐步增加。p75NTR、sortilin、proNGF与TH的相关性检验结果显示,p75NTR、sortilin、proNGF与TH细胞的减少成负相关性,相关系数分别为-0.988、-0.998、-0.993。FJC的增加与TH的减少呈负相关,相关系数为-0.999。
3. KA损伤后p75NTR上调启动细胞内凋亡信号途径
①KA损伤后启动JNK信号途径: c-jun属于caspase依赖的信号途径,研究发现KA损伤后黑质c-jun表达明显增加,c-jun/TH双标细胞数由10±1增加到20±2;Western Blot显示c-jun蛋白相对表达量由0.749±0.048增加到1.087±0.109。KA损伤后c-jun的磷酸化水平增高,p-c-jun/TH的双标细胞由26±2增加到65±4。
②KA损伤后诱导AIF表达增加: AIF属于caspase非依赖性的信号途径,发现AIF在KA损伤后细胞数明显增加,由正常195±3增加到243±14。而分布在黑质致密部AIF/TH阳性细胞由正常177±4减少到112±4。
结论
①首次发现p75NTR、sortilin在黑质多巴胺能神经元的表达与KA损伤后表达上调现象。
②p 75NTR、sortilin表达上调参与了KA损伤模型黑质多巴胺能神经元变性死亡过程。
③KA损伤模型中p75NTR、sortilin表达上调可能启动JNK和AIF等细胞内凋亡信号途径,导致神经元死亡。
本研究初步阐明了p75NTR、sortilin作为凋亡信号参与黑质多巴胺能神经元变性死亡的病理作用,为进一步揭示PD发生和发展机制、探索PD治疗的新靶点提供了重要依据。
Study purpose:
Parkinson's disease (PD) is a severe degenerative disorder that is characterized by massive dopaminergic neuronal loss in substantia nigra (SN). The pathogenesis of PD or mechanism of neuronal degeneration is still largely obscure. The p75 neurotrophin receptor (p75NTR), one key member of tumor necrosis receptor superfamily, has a low-affinity binding to mature neurotrophins, i.e. nerve growth factor (NGF), brain-derived neurotrophic factor and neurotrophin-3, and mediate neuronal cell survival, differentiation and neurite outgrowth. Rencent evidence has shown that p75NTR can in high affinity bind to the precursor of neurotrohpins such as pro-NGF, and trigger neuronal cell apoptosis by assistance of sortilin, a co-receptor of p75NTR. A line of evidence has shown that p75NTR plays important roles in controlling cell apoptosis in the developing or injury states of brain. While expression of p75NTR was upregulated in pathological condiations in the adult such as amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD), its abnormal upregulation is recognized to involve in neuronal degeneration in disease onset and progression of these neurodegenerative diseases.
However, it is still not known if p75NTR is also involved in pathogenesis of PD. By focusing on this question in this study, cellular localization of p75NTR and its co-receptor sortilin were first identified in the substantia nigra neurons. By using kainic acid (KA)-lesioned animal model, upregulated expression of p75NTR and sortilin was then examined, and their roles in inducing neuronal degeneration and triggering intracellular apoptosis signaling were investigated. The results of this study have provided important evidence to reveal significance of p75NTR and sortilin apoptotic signalling in disease progression and new intervention target for treatment of PD.
Material and Methods:
①KA-lesioned animal models were prepared by stereotaxic injection of KA into substantia nigra of adult rats.
②Reverse transcript polymerase chain reaction (RT-PCR) was quantitatively performed to examine expression and levels of p75NTR, sortilin, and proNGF mRNAs in the substantia nigra of control and KA-lesioned rats.
③Immunohistochemistry, double immunofluorescence and laser scanning confocal microscopy were used to localize p75NTR, sortilin, proNGF in the dopaminergic neurons in the substantia nigra.
④Western Blotting was quantitatively performed to confirm expression and levels of p75NTR, sortilin, proNGF proteins in the substantia nigra.
⑤Fluoro-Jade C (FJC), a specific stain for degenerating neurons, was carried out to visualizing neuronal degeneration in the substantia nigra of KA-lesioned rats.
⑥Analysis of intracellular apoptosis signaling was done to check activation of JNK, AIF signaling pathway in the substantia nigra neurons in KA-lesioned rats.
Main results:
1. Identification of p75NTR, sortilin expression in the dopaminergic neurons and their upregulation in the substantia nigra after KA insult
①Expression of p75NTR and sortilin in dopaminergic neurons was detected by using immunocytochemistry. In the midbrain sections, p75NTR or sortilin-positive neurons were observed, and they were mainly distributed in the substantia nigra pars compacta. Double immunofluorescence and laser scanning confocal microscopy confirmed that 47% TH-positive neurons expressed p75NTR, and sortilin was expressed in all TH-positive neuronal ones.
②Expression of p75NTR and sortilin mRNAs was further found in the substantia nigra by RT-PCR experiments. Results confirmed PCR bands of p75NTR, or sortilin mRNA in expected 309bp, or 438bp respectively.
③Up-regulation of p75NTR and sortilin was found in the substantia nigra of KA-lesioned animal model. Relative optical density of p75NTR increased from 0.489±0.079 at control to 1.06±0.11 at KA-lesion (p<0.01, t test), and sortilin increased from 0.724±0.056 at control to 1.226±0.078 at KA-lesion (p<0.01, t test). Expression of p75NTR increased into all TH-positive neurons, and sortilin-positive neurons increased from 204±4 to 293±13 in KA-lesion rats (p﹤0.01).
2.Up-regulation of p75NTR and sortilin expression induced degeneration of the dopaminergic neuron in the substnatia nigra after KA insult
①Colocalization of p75NTR and sortilin was confirmed in the substantia nigra neurons. Taken together with finding on p75NTR/TH, sortlin/TH double labeled neurons, it clearly appeared that p75NTR/sortilin was most colocalized in the dopaminergic neurons in the substantia nigra pars compacta, and these p75NTR/sortilin neurons constitute about 71.8% of total p75NTR ones.
②Expression of proNGF was further found in TH-positive neurons and GFAP-positive astrocytes in the substantia nigra. These proNGF/TH neurons were mostly distributed in the ventral tier of substantia nigra pars compacta, and proNGF/GFAP astrcytes were seen in the KA-lesion state.
③Up-regulated expression of proNGF was found in KA-lesioned substantia nigra which was in consistent with upregulation of p75NTR and sortilin. Results showed that relative optical density of proNGF mRNA increased from 0.18±0.037 at control to 0.703±0.059 at KA-lesion (p <0.01, t test). Cell counts indiacted that proNGF/TH neurons increased from 40±5 at control to 75±5 at KA-lesion (p﹤0.01).
④Quantitative and dynamic analysis were made on p75NTR, proNGF, sortilin, FJC, or TH-positive cells at time-points of d1, d3 and d7 afte KA-lesion. The results showed that p75NTR, sortilin, proNGF-positive cells increased gradually, but TH-positive neurons decreased, and at the same time FJC-positive cells increased. The relationship between p75NTR and TH, sortilin and TH, proNGF and TH were negative correlation, correlation coefficient were -0.988, -0.998, -0.993, respectively. The increase of FJC and decrease of TH was negative correlation, the correlation coefficient was -0.999.
3. Upregulation of p75NTR and sortilin expression might triger intracellular apoptotic JNK and AIF signals in KA-lesion state
①Activation of JNK signaling pathway was found in KA-lesion substantia nigra. It is well known that c-jun belongs to capase-dependent signaling pathway. The results showed that expression of c-jun and phosphorylation levels of c-jun increased dramatically in the substantia nigra after KA-lesion, c-jun/TH double labeled neurons increased from 10±1 at control to 20±2 at KA-lesion. Western blotting confirmed that relative density of c-jun protein increased from 0.749±0.048 at control to1.087±0.109 at KA-lesion (p<0.05). Besides, the p-c-jun/TH neurons increased from 26±2 at control to 65±4 at KA-lesion (p<0.01).
②Activation of AIF signal was also detected in the substantia nigra after KA-lesion. Evidence has shown that AIF belongs to capase-independent signaling pathway. This result indicated that AIF expression was significantly up-regulated in KA-lesioned substantia nigra. In the nigra region, AIF-positve increased from 195±3 at control to 243±14 at KA-lesion. On the other hand, AIF/TH positive neurons decreased from 177±4 at control to 112±4 at KA-lesion, indicating some AIF/TH neurons was died after KA-insult.
Preliminary conclusion
①Expression of p75NTR, sortilin was first identified in dopaminergic neurons of substantia nigra in this study, and upregulated levels were found in KA injury state.
②Up-regulation of p75NTR and sortilin appeared to induce degenerative death of dopaminergic neurons of the substantia nigra in KA-lesioned animal model.
③Up-regulated p75NTR and sortilin might be involved in activation of intracellular JNK and AIF signaling in substantia nigra of KA-lesioned rats.
These data has provided evidence that p75NTR, sortilin apoptotic signalling may be involved in inducing degeneration of dopaminergic neuron in the substantia nigra. This study also suggested that p75NTR may play important role in pathogenesis or disease progression of PD and represent new intervention target for treatment of PD.
帕金森(Parkinson’s disease,PD)是以黑质多巴胺能神经元大量变性死亡为特征的严重神经退行性疾病,其神经元变性死亡的发生原因与病理机制,仍然是制约PD临床治疗的关键问题。研究表明p75神经营养素受体(p75 neurotrophin receptor, p75NTR)是肿瘤坏死因子受体家族的重要成员,以低亲和力与神经营养素(neurotrophins,NTs)结合,介导神经元存活、分化与髓鞘形成。近来发现NT前体分子如神经生长因子前体(pro-nerve growth factor, proNGF)能够以高亲和力结合p75NTR,并通过辅助受体sortilin的协助启动细胞凋亡,在脑发育和脑损伤神经元的凋亡中发挥重要作用。成年后p75NTR主要在某些病理状态下表达,如脊髓侧索硬化症(ALS)和阿尔茨海默病(AD)等,异常表达的p75NTR参与疾病过程中的神经元变性或细胞凋亡。
但目前p75NTR与PD病理关系问题,仍是研究空白,本研究针对这一问题,探讨p75NTR与辅助受体sortilin在黑质的表达、细胞定位、KA损伤模型的动态变化、及其参与中脑黑质多巴胺能神经元变性死亡的病理作用,为揭示p75NTR、sortilin凋亡信号参与PD病理发展机制和疾病治疗新靶点提供依据。
研究方法
①采用红藻氨酸(kainic acid,KA)立体定位注射黑质建立兴奋性毒性损伤动物模型。
②通过半定量聚合酶链式反应(RT-PCR)检测p75NTR、sortilin、proNGFmRNA在黑质表达及其损伤后的变化。
③免疫细胞化学、双标记、及激光共聚焦显微镜观察等方法,研究p75NTR、sortilin、proNGF在黑质多巴胺能神经元的定位。
④Western Blot分析p75NTR、sortilin、proNGF蛋白在黑质的表达情况与水平变化。
⑤F luoro-Jade C(FJC)染色方法显示和计数分析黑质神经元变性死亡。
⑥细胞内凋亡信号的分析初步观察JNK、AIF细胞内信号通路的参与问题。
主要结果
1.发现p75NTR、sortilin在黑质多巴胺能神经元的表达,KA损伤后导致其表达上调。
①免疫细胞化学研究发现黑质p75NTR和sortilin的表达:在中脑黑质切片上,检测到p75NTR、sortilin阳性神经元,它们主要分布在黑质的致密部。双标记染色与激光共聚焦显微镜观察证明47%TH阳性神经元表达p75NTR,而sortilin表达于全部的TH阳性神经元。
②RT-PCR实验证明黑质p75NTR、sortilin mRNA的表达:RT-PCR结果发现p75NTR、sortilin mRNA阳性条带,p75NTR条带大小为309bp,sortilin条带大小为438bp,与预期的结果相符。
③KA损伤导致黑质p75NTR、sortilin表达上调: p75NTR mRNA相对光密度由正常黑质的0.489±0.079上升为1.06±0.11(p﹤0.01,t test);sortilin mRNA相对光密度由正常黑质的0.724±0.056上升为1.226±0.078(p﹤0.01,t test);KA损伤后p75NTR上调表达于所有的TH免疫阳性神经元,sortilin的细胞数由204±4上升到293±13,具有统计学差异(p﹤0.01)。
2.p75NTR、sortilin表达上调参与KA损伤模型黑质多巴胺能神经元变性死亡
①p 75NTR、sortilin共存于黑质多巴胺能神经元:在p75NTR/TH、sortilin/TH双标结果基础上,进一步观察到大量的p75NTR/sortilin双标记神经元分布在黑质致密部,这些双标记神经元占全部p75NTR神经元的71.8%。
②proNGF免疫阳性存在黑质神经元及星形胶质细胞:免疫细胞化学结果显示proNGF定位于黑质致密部腹侧带的多巴胺神经元,并且发现proNGF定位于激活的星形胶质细胞。
③p roNGF在KA损伤后呈现与p75NTR、sortilin共同上调现象: proNGF mRNA相对光密度由正常黑质0.18±0.037上升为0.703±0.059(p﹤0.01,t test); proNGF/TH双标细胞数由正常黑质40±5,增加到75±5,具有统计学差异(p﹤0.01)。
④p 75NTR、sortilin、proNGF、FJC及TH阳性细胞在KA损伤后的d1、d3、d7天时的动态变化:细胞计数结果显示p75NTR、sortilin、proNGF逐渐增加,TH神经元逐渐减少,同时FJC标记的变性神经元逐步增加。p75NTR、sortilin、proNGF与TH的相关性检验结果显示,p75NTR、sortilin、proNGF与TH细胞的减少成负相关性,相关系数分别为-0.988、-0.998、-0.993。FJC的增加与TH的减少呈负相关,相关系数为-0.999。
3. KA损伤后p75NTR上调启动细胞内凋亡信号途径
①KA损伤后启动JNK信号途径: c-jun属于caspase依赖的信号途径,研究发现KA损伤后黑质c-jun表达明显增加,c-jun/TH双标细胞数由10±1增加到20±2;Western Blot显示c-jun蛋白相对表达量由0.749±0.048增加到1.087±0.109。KA损伤后c-jun的磷酸化水平增高,p-c-jun/TH的双标细胞由26±2增加到65±4。
②KA损伤后诱导AIF表达增加: AIF属于caspase非依赖性的信号途径,发现AIF在KA损伤后细胞数明显增加,由正常195±3增加到243±14。而分布在黑质致密部AIF/TH阳性细胞由正常177±4减少到112±4。
结论
①首次发现p75NTR、sortilin在黑质多巴胺能神经元的表达与KA损伤后表达上调现象。
②p 75NTR、sortilin表达上调参与了KA损伤模型黑质多巴胺能神经元变性死亡过程。
③KA损伤模型中p75NTR、sortilin表达上调可能启动JNK和AIF等细胞内凋亡信号途径,导致神经元死亡。
本研究初步阐明了p75NTR、sortilin作为凋亡信号参与黑质多巴胺能神经元变性死亡的病理作用,为进一步揭示PD发生和发展机制、探索PD治疗的新靶点提供了重要依据。
Study purpose:
Parkinson's disease (PD) is a severe degenerative disorder that is characterized by massive dopaminergic neuronal loss in substantia nigra (SN). The pathogenesis of PD or mechanism of neuronal degeneration is still largely obscure. The p75 neurotrophin receptor (p75NTR), one key member of tumor necrosis receptor superfamily, has a low-affinity binding to mature neurotrophins, i.e. nerve growth factor (NGF), brain-derived neurotrophic factor and neurotrophin-3, and mediate neuronal cell survival, differentiation and neurite outgrowth. Rencent evidence has shown that p75NTR can in high affinity bind to the precursor of neurotrohpins such as pro-NGF, and trigger neuronal cell apoptosis by assistance of sortilin, a co-receptor of p75NTR. A line of evidence has shown that p75NTR plays important roles in controlling cell apoptosis in the developing or injury states of brain. While expression of p75NTR was upregulated in pathological condiations in the adult such as amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD), its abnormal upregulation is recognized to involve in neuronal degeneration in disease onset and progression of these neurodegenerative diseases.
However, it is still not known if p75NTR is also involved in pathogenesis of PD. By focusing on this question in this study, cellular localization of p75NTR and its co-receptor sortilin were first identified in the substantia nigra neurons. By using kainic acid (KA)-lesioned animal model, upregulated expression of p75NTR and sortilin was then examined, and their roles in inducing neuronal degeneration and triggering intracellular apoptosis signaling were investigated. The results of this study have provided important evidence to reveal significance of p75NTR and sortilin apoptotic signalling in disease progression and new intervention target for treatment of PD.
Material and Methods:
①KA-lesioned animal models were prepared by stereotaxic injection of KA into substantia nigra of adult rats.
②Reverse transcript polymerase chain reaction (RT-PCR) was quantitatively performed to examine expression and levels of p75NTR, sortilin, and proNGF mRNAs in the substantia nigra of control and KA-lesioned rats.
③Immunohistochemistry, double immunofluorescence and laser scanning confocal microscopy were used to localize p75NTR, sortilin, proNGF in the dopaminergic neurons in the substantia nigra.
④Western Blotting was quantitatively performed to confirm expression and levels of p75NTR, sortilin, proNGF proteins in the substantia nigra.
⑤Fluoro-Jade C (FJC), a specific stain for degenerating neurons, was carried out to visualizing neuronal degeneration in the substantia nigra of KA-lesioned rats.
⑥Analysis of intracellular apoptosis signaling was done to check activation of JNK, AIF signaling pathway in the substantia nigra neurons in KA-lesioned rats.
Main results:
1. Identification of p75NTR, sortilin expression in the dopaminergic neurons and their upregulation in the substantia nigra after KA insult
①Expression of p75NTR and sortilin in dopaminergic neurons was detected by using immunocytochemistry. In the midbrain sections, p75NTR or sortilin-positive neurons were observed, and they were mainly distributed in the substantia nigra pars compacta. Double immunofluorescence and laser scanning confocal microscopy confirmed that 47% TH-positive neurons expressed p75NTR, and sortilin was expressed in all TH-positive neuronal ones.
②Expression of p75NTR and sortilin mRNAs was further found in the substantia nigra by RT-PCR experiments. Results confirmed PCR bands of p75NTR, or sortilin mRNA in expected 309bp, or 438bp respectively.
③Up-regulation of p75NTR and sortilin was found in the substantia nigra of KA-lesioned animal model. Relative optical density of p75NTR increased from 0.489±0.079 at control to 1.06±0.11 at KA-lesion (p<0.01, t test), and sortilin increased from 0.724±0.056 at control to 1.226±0.078 at KA-lesion (p<0.01, t test). Expression of p75NTR increased into all TH-positive neurons, and sortilin-positive neurons increased from 204±4 to 293±13 in KA-lesion rats (p﹤0.01).
2.Up-regulation of p75NTR and sortilin expression induced degeneration of the dopaminergic neuron in the substnatia nigra after KA insult
①Colocalization of p75NTR and sortilin was confirmed in the substantia nigra neurons. Taken together with finding on p75NTR/TH, sortlin/TH double labeled neurons, it clearly appeared that p75NTR/sortilin was most colocalized in the dopaminergic neurons in the substantia nigra pars compacta, and these p75NTR/sortilin neurons constitute about 71.8% of total p75NTR ones.
②Expression of proNGF was further found in TH-positive neurons and GFAP-positive astrocytes in the substantia nigra. These proNGF/TH neurons were mostly distributed in the ventral tier of substantia nigra pars compacta, and proNGF/GFAP astrcytes were seen in the KA-lesion state.
③Up-regulated expression of proNGF was found in KA-lesioned substantia nigra which was in consistent with upregulation of p75NTR and sortilin. Results showed that relative optical density of proNGF mRNA increased from 0.18±0.037 at control to 0.703±0.059 at KA-lesion (p <0.01, t test). Cell counts indiacted that proNGF/TH neurons increased from 40±5 at control to 75±5 at KA-lesion (p﹤0.01).
④Quantitative and dynamic analysis were made on p75NTR, proNGF, sortilin, FJC, or TH-positive cells at time-points of d1, d3 and d7 afte KA-lesion. The results showed that p75NTR, sortilin, proNGF-positive cells increased gradually, but TH-positive neurons decreased, and at the same time FJC-positive cells increased. The relationship between p75NTR and TH, sortilin and TH, proNGF and TH were negative correlation, correlation coefficient were -0.988, -0.998, -0.993, respectively. The increase of FJC and decrease of TH was negative correlation, the correlation coefficient was -0.999.
3. Upregulation of p75NTR and sortilin expression might triger intracellular apoptotic JNK and AIF signals in KA-lesion state
①Activation of JNK signaling pathway was found in KA-lesion substantia nigra. It is well known that c-jun belongs to capase-dependent signaling pathway. The results showed that expression of c-jun and phosphorylation levels of c-jun increased dramatically in the substantia nigra after KA-lesion, c-jun/TH double labeled neurons increased from 10±1 at control to 20±2 at KA-lesion. Western blotting confirmed that relative density of c-jun protein increased from 0.749±0.048 at control to1.087±0.109 at KA-lesion (p<0.05). Besides, the p-c-jun/TH neurons increased from 26±2 at control to 65±4 at KA-lesion (p<0.01).
②Activation of AIF signal was also detected in the substantia nigra after KA-lesion. Evidence has shown that AIF belongs to capase-independent signaling pathway. This result indicated that AIF expression was significantly up-regulated in KA-lesioned substantia nigra. In the nigra region, AIF-positve increased from 195±3 at control to 243±14 at KA-lesion. On the other hand, AIF/TH positive neurons decreased from 177±4 at control to 112±4 at KA-lesion, indicating some AIF/TH neurons was died after KA-insult.
Preliminary conclusion
①Expression of p75NTR, sortilin was first identified in dopaminergic neurons of substantia nigra in this study, and upregulated levels were found in KA injury state.
②Up-regulation of p75NTR and sortilin appeared to induce degenerative death of dopaminergic neurons of the substantia nigra in KA-lesioned animal model.
③Up-regulated p75NTR and sortilin might be involved in activation of intracellular JNK and AIF signaling in substantia nigra of KA-lesioned rats.
These data has provided evidence that p75NTR, sortilin apoptotic signalling may be involved in inducing degeneration of dopaminergic neuron in the substantia nigra. This study also suggested that p75NTR may play important role in pathogenesis or disease progression of PD and represent new intervention target for treatment of PD.
引文
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