CDK5磷酸化Raf激酶抑制蛋白在帕金森病中的研究进展
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摘要
随着人口老龄化的加重，神经退行性疾病得到了越来越多的重视。在包括阿尔兹海默式症（Alzheimer’s disease, AD）、帕金森病（Parkinson’s disease,PD）及亨廷顿病（Huntinton’s disease, HD）等的多种神经退行性疾病中，神经元的过度死亡是疾病的共同表现，也是出现多种神经系统病理症状的主要原因。神经退行性疾病中关于神经元死亡增多的机制研究已经获得了一些结论，但在分子机制方面仍有许多问题尚未得到回答。在研究神经元死亡机制的过程中，神经元细胞周期再进入（cell cycle re-entry）这一概念的重要性逐渐浮现出来。细胞周期是可分裂细胞维持其生长与增殖状态的重要生理事件，但成熟神经元是无法进入细胞周期的。当神经元在病理状态下进入了细胞周期时，即被称为细胞周期再进入。神经元无法通过细胞周期来进行分裂，因此细胞周期再进入后可直接通过凋亡相关的分子机制来介导神经元发生死亡。
细胞周期的运行受到多条信号通路的调控，而丝裂原激活的激酶信号通路（ERK/MAPK cascade）是其中的重要部分。在可增殖细胞中，ERK/MAPK通路主要介导了细胞由G1期进入S期以及纺锤体形成等过程；而对神经元来说，进入S期即代表发生了细胞周期再进入，细胞会难以避免地走向死亡。因此，研究ERK/MAPK通路的活性调控对研究神经元的细胞周期及死亡是具有重要意义的。
在关注ERK通路活性时，我们将Raf激酶抑制蛋白（Raf kinase inhibitorprotein，RKIP）作为目的分子，后者是ERK通路的生理性抑制因子，通过结合并抑制Raf-1活性来发挥作用。RKIP表达的下调已被证实参与多种恶性肿瘤发生与发展过程，但其下调的分子机制尚不明确。RKIP在脑组织中高表达，但在神经系统及神经退行性疾病中的作用也报道不多。
为了研究RKIP蛋白影响ERK通路活性的方式，我们又注意到另一个重要分子，细胞周期素依赖性蛋白激酶5（cyclin-dependent kinase5, CDK5）。CDK5的活性呈神经系统特异性分布，通过磷酸化多种底物来调控神经元的发育、轴突导向、突触形成、迁移等多种重要事件。因此，本论文拟以帕金森病为神经退行性疾病模型，研究在其病变过程中，CDK5对RKIP蛋白是否存在调节作用，以及该调节机制是否对ERK/MAPK通路的活性和多巴胺能神经元存活的情况产生影响。
本文首先在体外和细胞水平验证了RKIP蛋白是CDK5的磷酸化底物，且磷酸化RKIP与Raf-1的结合能力显著低于未磷酸化时，表明RKIP的T42位磷酸化可介导RKIP与Raf-1解离。一方面，磷酸化修饰可以诱导RKIP蛋白自身通过分子伴侣介导的自噬途径（chaperone-mediated autophagy, CMA）降解，且RKIP序列中的“179KLYEQ183”结构域是CMA的作用靶点，由分子伴侣Hsc70识别并结合该结构域，并将RKIP携带至溶酶体进行降解。另一方面，在与磷酸化RKIP解离后，Raf-1的激酶活性得到解放，对神经元的检测表明此时磷酸化MEK、磷酸化ERK的表达都上调，说明ERK通路下游信号出现了级联式激活，并最终会产生细胞学效应。
接下来，实验结果表明ERK通路激活时，进入S期的神经元数量增多，表明出现了细胞周期再进入现象。此时，神经元也出现了死亡增多，而抑制CDK5活性或ERK通路活性均对神经元有保护作用，表明细胞周期再进入现象参与介导了神经元的死亡。在帕金森病的神经元模型中，我们同样发现多巴胺能神经元也会出现RKIP磷酸化增强、ERK通路激活相关的细胞周期再进入，以及继发的神经元死亡。最后，无论是MPTP诱导的还是转基因的帕金森病模型鼠，其中脑组织都出现了RKIP磷酸化水平上调，ERK通路过度激活，且在老年PD鼠中存在明显的RKIP水平降低。这些结果表明，RKIP磷酸化介导的ERK通路激活导致了多巴胺能神经元细胞周期再进入，并参与了神经元死亡的过程。
帕金森病中神经元的死亡机制一直受到关注，而此处我们以RKIP这一分子为线索，将CDK5激酶、ERK/MAPK通路、自噬途径及细胞周期再进入等概念在PD中的作用串联起来，提出了以CDK5异常激活、RKIP磷酸化增多为前提，继之以RKIP自噬增强、ERK通路过度激活和细胞周期再进入这一神经元死亡的新机制，拓展了对PD中神经元死亡机制的理解，也为PD这一神经退行性疾病的治疗靶点的探索提供了新的研究思路和理论基础。
Neurodegenerative diseases catch more and more attentions in these years,accompanied with the aging of population. Loss of neurons is a common pathologicalevent in all neurodegenerative diseases such as Alzheimer's disease (AD),Parkinson's disease (PD) and Huntington's disease (HD), and the neuronal loss isresponsible for many behavioral symptoms of these diseases. There were a lot ofreports about the mechanisms involved in the neuronal loss of neurodegenerativediseases, but the details are still under exploration. The significance of neuronal cellcycle re-entry has been noticed in the studies of neuronal death recently. Cell cycle isa crucial event in normal division and differentiation of proliferative cells, but post-mitotic neurons are not allowed to enter cell cycle in physiological circumstances.Once a neuron enters cell cycle in a stimulated situation, it is called “cell cycle re-entry”, and the neuron is doomed because the entry of cell cycle would triggerapoptotic signals rather than cell division signals in a post-mitotic neuron.
Cell cycle must be delicately regulated by several signaling pathways together, andmitogen-activated protein kinases cascade (ERK/MAPK cascade) plays an improtantrole in this process. ERK/MAPK pathway normally mediates the G1/S transition andspindle assembly checkpoint in proliferative cells, but cell death is usually inevitableonce a neuron enters the S-phase. So the study of the regulation of ERK cascade isquite valuable for the understanding of cell cycle re-entry and cell death in neurons.
Raf kinase inhibitor protein (RKIP) is a physiological inhibitor of ERK/MAPKpathway, interacting with Raf-1and blocking its activity. Downregulation of RKIPhas been reported to correlate with many cancers, but the mechanisms that underliethis downregulation is still poorly understood. Plus, the expression of RKIP is high inthe brain, but its functions in the nervous system and neurodegenerative diseases arenot clear yet.
To explore the regulation of RKIP in neurons, we added another protein in thesystem, cyclin-dependent kinase5(CDK5). The activity of CDK5is highly specific inthe nervous system, and CDK5controls many important events in neurons such asdifferentiation, axon guidance, synaptic plasticity and migration by means ofphosphorylating a string of substrates. In this research, we studied the interaction between CDK5and RKIP, discussed the influence of this interaction on the activity ofERK cascade and mortality of dopaminergic neurons in Parkinson's disease.
Firstly, we identified RKIP as a substrate of CDK5, and the phosphorylation ofRKIP at T42attenuated its affinity to Raf-1, so the phosphorylation of RKIP mediatedthe release of Raf-1from RKIP. On one hand, T42phosphorylation promotes theexposure and recognition of the target motif “179KLYEQ183” in C-terminus of RKIPby chaperone Hsc70and the subsequent degradation of RKIP itself via chaperone-mediated autophagy (CMA). On the other hand, the release of Raf-1rescued itskinase activity, and the signals of p-MEK and p-ERK were both increased in neuronsin such circumstance, suggesting the activation of downstream signals of ERKcascade.
In the next section, we demonstrated that the number of BrdU+neurons increasedwhen ERK cascade was activated, indicating the neuronal cell cycle re-entry. Theneuronal mortality also rised in the mean time, while inhibition of CDK5or ERKpathway was helpful in cell survival. So the phenomenon of cell cycle re-entryparticipated in the neuronal death. Furthermore, in the cellular model of Parkinson'sdisease, we also observed the upregulation of phosphorylated RKIP, the cell cycle re-entry related to activation of ERK cascade, and subsequent cell death in dopaminergicneurons. And in the brain of both MPTP-induced and transgenic models of PD, wefound an increase in p-RKIP and activation of ERK cascade, plus a downregulation ofRKIP in PD mice of old age. Taken together, we demonstrate that phosphorylation ofRKIP is involved in the overactivation of the ERK/MAPK cascade, leading to S-phase re-entry and neuronal loss in Parkinson's disease.
The mechanisms that underlie neuronal loss in Parkinson's disease have attractedattention for years, and in the current study we supplied a system which united RKIP,CDK5, ERK cascade, autophagy, cell cycle re-entry together in the context of PD. Wedemostrated that after overactivation of CDK5and enhanced phosphorylation ofRKIP, the degradation of RKIP was induced and ERK cascade was overactivated,followed by neuronal cell cycle re-entry and neuronal death. These findings provideevidence for the role of the CDK5/RKIP/ERK pathway in PD pathogenesis andsuggest that this pathway may be a suitable therapeutic target in PD.
细胞周期的运行受到多条信号通路的调控，而丝裂原激活的激酶信号通路（ERK/MAPK cascade）是其中的重要部分。在可增殖细胞中，ERK/MAPK通路主要介导了细胞由G1期进入S期以及纺锤体形成等过程；而对神经元来说，进入S期即代表发生了细胞周期再进入，细胞会难以避免地走向死亡。因此，研究ERK/MAPK通路的活性调控对研究神经元的细胞周期及死亡是具有重要意义的。
在关注ERK通路活性时，我们将Raf激酶抑制蛋白（Raf kinase inhibitorprotein，RKIP）作为目的分子，后者是ERK通路的生理性抑制因子，通过结合并抑制Raf-1活性来发挥作用。RKIP表达的下调已被证实参与多种恶性肿瘤发生与发展过程，但其下调的分子机制尚不明确。RKIP在脑组织中高表达，但在神经系统及神经退行性疾病中的作用也报道不多。
为了研究RKIP蛋白影响ERK通路活性的方式，我们又注意到另一个重要分子，细胞周期素依赖性蛋白激酶5（cyclin-dependent kinase5, CDK5）。CDK5的活性呈神经系统特异性分布，通过磷酸化多种底物来调控神经元的发育、轴突导向、突触形成、迁移等多种重要事件。因此，本论文拟以帕金森病为神经退行性疾病模型，研究在其病变过程中，CDK5对RKIP蛋白是否存在调节作用，以及该调节机制是否对ERK/MAPK通路的活性和多巴胺能神经元存活的情况产生影响。
本文首先在体外和细胞水平验证了RKIP蛋白是CDK5的磷酸化底物，且磷酸化RKIP与Raf-1的结合能力显著低于未磷酸化时，表明RKIP的T42位磷酸化可介导RKIP与Raf-1解离。一方面，磷酸化修饰可以诱导RKIP蛋白自身通过分子伴侣介导的自噬途径（chaperone-mediated autophagy, CMA）降解，且RKIP序列中的“179KLYEQ183”结构域是CMA的作用靶点，由分子伴侣Hsc70识别并结合该结构域，并将RKIP携带至溶酶体进行降解。另一方面，在与磷酸化RKIP解离后，Raf-1的激酶活性得到解放，对神经元的检测表明此时磷酸化MEK、磷酸化ERK的表达都上调，说明ERK通路下游信号出现了级联式激活，并最终会产生细胞学效应。
接下来，实验结果表明ERK通路激活时，进入S期的神经元数量增多，表明出现了细胞周期再进入现象。此时，神经元也出现了死亡增多，而抑制CDK5活性或ERK通路活性均对神经元有保护作用，表明细胞周期再进入现象参与介导了神经元的死亡。在帕金森病的神经元模型中，我们同样发现多巴胺能神经元也会出现RKIP磷酸化增强、ERK通路激活相关的细胞周期再进入，以及继发的神经元死亡。最后，无论是MPTP诱导的还是转基因的帕金森病模型鼠，其中脑组织都出现了RKIP磷酸化水平上调，ERK通路过度激活，且在老年PD鼠中存在明显的RKIP水平降低。这些结果表明，RKIP磷酸化介导的ERK通路激活导致了多巴胺能神经元细胞周期再进入，并参与了神经元死亡的过程。
帕金森病中神经元的死亡机制一直受到关注，而此处我们以RKIP这一分子为线索，将CDK5激酶、ERK/MAPK通路、自噬途径及细胞周期再进入等概念在PD中的作用串联起来，提出了以CDK5异常激活、RKIP磷酸化增多为前提，继之以RKIP自噬增强、ERK通路过度激活和细胞周期再进入这一神经元死亡的新机制，拓展了对PD中神经元死亡机制的理解，也为PD这一神经退行性疾病的治疗靶点的探索提供了新的研究思路和理论基础。
Neurodegenerative diseases catch more and more attentions in these years,accompanied with the aging of population. Loss of neurons is a common pathologicalevent in all neurodegenerative diseases such as Alzheimer's disease (AD),Parkinson's disease (PD) and Huntington's disease (HD), and the neuronal loss isresponsible for many behavioral symptoms of these diseases. There were a lot ofreports about the mechanisms involved in the neuronal loss of neurodegenerativediseases, but the details are still under exploration. The significance of neuronal cellcycle re-entry has been noticed in the studies of neuronal death recently. Cell cycle isa crucial event in normal division and differentiation of proliferative cells, but post-mitotic neurons are not allowed to enter cell cycle in physiological circumstances.Once a neuron enters cell cycle in a stimulated situation, it is called “cell cycle re-entry”, and the neuron is doomed because the entry of cell cycle would triggerapoptotic signals rather than cell division signals in a post-mitotic neuron.
Cell cycle must be delicately regulated by several signaling pathways together, andmitogen-activated protein kinases cascade (ERK/MAPK cascade) plays an improtantrole in this process. ERK/MAPK pathway normally mediates the G1/S transition andspindle assembly checkpoint in proliferative cells, but cell death is usually inevitableonce a neuron enters the S-phase. So the study of the regulation of ERK cascade isquite valuable for the understanding of cell cycle re-entry and cell death in neurons.
Raf kinase inhibitor protein (RKIP) is a physiological inhibitor of ERK/MAPKpathway, interacting with Raf-1and blocking its activity. Downregulation of RKIPhas been reported to correlate with many cancers, but the mechanisms that underliethis downregulation is still poorly understood. Plus, the expression of RKIP is high inthe brain, but its functions in the nervous system and neurodegenerative diseases arenot clear yet.
To explore the regulation of RKIP in neurons, we added another protein in thesystem, cyclin-dependent kinase5(CDK5). The activity of CDK5is highly specific inthe nervous system, and CDK5controls many important events in neurons such asdifferentiation, axon guidance, synaptic plasticity and migration by means ofphosphorylating a string of substrates. In this research, we studied the interaction between CDK5and RKIP, discussed the influence of this interaction on the activity ofERK cascade and mortality of dopaminergic neurons in Parkinson's disease.
Firstly, we identified RKIP as a substrate of CDK5, and the phosphorylation ofRKIP at T42attenuated its affinity to Raf-1, so the phosphorylation of RKIP mediatedthe release of Raf-1from RKIP. On one hand, T42phosphorylation promotes theexposure and recognition of the target motif “179KLYEQ183” in C-terminus of RKIPby chaperone Hsc70and the subsequent degradation of RKIP itself via chaperone-mediated autophagy (CMA). On the other hand, the release of Raf-1rescued itskinase activity, and the signals of p-MEK and p-ERK were both increased in neuronsin such circumstance, suggesting the activation of downstream signals of ERKcascade.
In the next section, we demonstrated that the number of BrdU+neurons increasedwhen ERK cascade was activated, indicating the neuronal cell cycle re-entry. Theneuronal mortality also rised in the mean time, while inhibition of CDK5or ERKpathway was helpful in cell survival. So the phenomenon of cell cycle re-entryparticipated in the neuronal death. Furthermore, in the cellular model of Parkinson'sdisease, we also observed the upregulation of phosphorylated RKIP, the cell cycle re-entry related to activation of ERK cascade, and subsequent cell death in dopaminergicneurons. And in the brain of both MPTP-induced and transgenic models of PD, wefound an increase in p-RKIP and activation of ERK cascade, plus a downregulation ofRKIP in PD mice of old age. Taken together, we demonstrate that phosphorylation ofRKIP is involved in the overactivation of the ERK/MAPK cascade, leading to S-phase re-entry and neuronal loss in Parkinson's disease.
The mechanisms that underlie neuronal loss in Parkinson's disease have attractedattention for years, and in the current study we supplied a system which united RKIP,CDK5, ERK cascade, autophagy, cell cycle re-entry together in the context of PD. Wedemostrated that after overactivation of CDK5and enhanced phosphorylation ofRKIP, the degradation of RKIP was induced and ERK cascade was overactivated,followed by neuronal cell cycle re-entry and neuronal death. These findings provideevidence for the role of the CDK5/RKIP/ERK pathway in PD pathogenesis andsuggest that this pathway may be a suitable therapeutic target in PD.
引文
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