CDK5 的异常激活触发阿尔茨海默病模型中的多种神经退行性途径
中文名称
通路描述
后分裂期神经元没有活跃的细胞周期。然而，这些神经元中 Cyclin 依赖性激酶 -5 (CDK5) 活性的失调可以异常激活细胞周期的各种组件，导致神经元死亡 (Chang et al. 2012)。随机激活细胞周期蛋白已被证明在几种神经退行性疾病的发病机制中起关键作用 (Yang et al. 2003, Lopes et al. 2009)。CDK5 不由经典细胞周期蛋白激活，而是与其特定的伴侣蛋白 CDK5R1 和 CDK5R2（分别称为 p35 和 p39）结合 (Tsai et al. 1994, Tang et al. 1995)。p35 的表达几乎遍布全身，而 p39 主要在中枢神经系统表达。各种神经毒性 insults 如β-淀粉样蛋白 (A-beta)、缺血、兴奋性毒性及氧化应激会破坏神经元内的钙稳态，从而激活钙蛋白酶，将 p35 切割成 p25 和 p10 (Lee et al. 2000)。p25 的半衰期比 p35 长六倍，且缺乏膜锚定信号，导致 CDK5:p25 复合物在细胞质和细胞核中发生组成性激活和错定位。在那里，CDK5:p25 能够访问并磷酸化各种非典型靶标，触发一系列神经毒性途径，最终导致神经元死亡。其中一种神经毒性途径涉及 CDK5 介导的细胞周期蛋白的随机激活，最终导致神经元死亡。暴露于寡聚体β-淀粉样蛋白 (1-42) 的初级皮层神经元会因 p25 形成而过度激活 CDK5，后者进而磷酸化 CDC25A、CDC25B 和 CDC25C。CDK5 磷酸化 CDC25A 于 S40、S116 和 S261；CDC25B 于 S50、T69、S160、S321 和 S470；以及 CDC25C 于 T48、T67、S122、T130、S168 和 S214。CDK5 介导的 CDC25A、CDC25B 和 CDC25C 的磷酸化不仅增加了它们的磷酸酶活性，还促进了它们从 14-3-3 抑制性结合中的释放。CDC25A、CDC25B 和 CDC25C 进而激活 CDK1、CDK2 和 CDK4 激酶，导致神经元死亡。与这一机制一致，与年龄匹配的对照相比，人类阿尔茨海默病 (AD) 临床样本中观察到更高的 CDC25A、CDC25B 和 CDC25C 活性。抑制 CDC25 异构体可赋予β-淀粉样蛋白毒性神经保护，这强调了该途径在 AD 发病机制中的贡献。
英文描述
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models Post-mitotic neurons do not have an active cell cycle. However, deregulation of Cyclin Dependent Kinase-5 (CDK5) activity in these neurons can aberrantly activate various components of cell cycle leading to neuronal death (Chang et al. 2012). Random activation of cell cycle proteins has been shown to play a key role in the pathogenesis of several neurodegenerative disorders (Yang et al. 2003, Lopes et al. 2009). CDK5 is not activated by the canonical cyclins, but binds to its own specific partners, CDK5R1 and CDK5R2 (aka p35 and p39, respectively) (Tsai et al. 1994, Tang et al. 1995). Expression of p35 is nearly ubiquitous, whereas p39 is largely expressed in the central nervous system. A variety of neurotoxic insults such as beta-amyloid (A-beta), ischemia, excitotoxicity and oxidative stress disrupt the intracellular calcium homeostasis in neurons, thereby leading to the activation of calpain, which cleaves p35 into p25 and p10 (Lee et al. 2000). p25 has a six-fold longer half-life compared to p35 and lacks the membrane anchoring signal, which results in its constitutive activation and mislocalization of the CDK5:p25 complex to the cytoplasm and the nucleus. There, CDK5:p25 is able to access and phosphorylate a variety of atypical targets, triggering a cascade of neurotoxic pathways that culminate in neuronal death. One such neurotoxic pathway involves CDK5-mediated random activation of cell cycle proteins which culminate in neuronal death. Exposure of primary cortical neurons to oligomeric beta-amyloid (1-42) hyper-activates CDK5 due to p25 formation, which in turn phosphorylates CDC25A, CDC25B and CDC25C. CDK5 phosphorylates CDC25A at S40, S116 and S261; CDC25B at S50, T69, S160, S321 and S470; and CDC25C at T48, T67, S122, T130, S168 and S214. CDK5-mediated phosphorylation of CDC25A, CDC25B and CDC25C not only increases their phosphatase activities but also facilitates their release from 14-3-3 inhibitory binding. CDC25A, CDC25B and CDC25C in turn activate CDK1, CDK2 and CDK4 kinases causing neuronal death. Consistent with this mechanism, higher CDC25A, CDC25B and CDC25C activities were observed in human Alzheimer's disease (AD) clinical samples, as compared to age-matched controls. Inhibition of CDC25 isoforms confers neuroprotection to beta-amyloid toxicity, which underscores the contribution of this pathway to AD pathogenesis
所含基因
22 个基因