Deregulated Cdk5 triggers aberrant activation of cell cycle kinases and phosphatases inducing neuronal death
Deregulated Cdk5 triggers aberrant activation of cell cycle kinases and phosphatases inducing neuronal death
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DOI：
10.1242/jcs.108183
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发表时间：
2012-11-01
影响因子：
4
通讯作者：
Shah, Kavita
中科院分区：
文献类型：
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作者：
Chang, Kuei-Hua;Vincent, Fabien;Shah, Kavita
细胞周期蛋白的异常激活被认为在阿尔茨海默病（AD）的发病机制中起着关键作用;尽管，导致其在患病神经元中激活的分子机制仍然难以捉摸。本研究的目的是研究β-淀粉样蛋白（1-42）（A β（1 - 42））诱导的神经毒性中Cdk 5失调和细胞周期再激活之间的机制联系。使用化学遗传学方法，我们确定Cdc 25 A，Cdc 25 B和Cdc 25 C作为小鼠脑裂解液中的直接Cdk 5底物。我们发现，去调节Cdk 5直接磷酸化Cdc 25 A，Cdc 25 B和Cdc 25 C在多个网站，这不仅增加了他们的磷酸酶活性，但也有利于他们从14-3-3抑制结合释放。Cdc 25 A、Cdc 25 B和Cdc 25 C依次激活Cdk 1、Cdk 2和Cdk 4激酶，导致神经元死亡。Cdk 5的选择性抑制消除了A β（1-42）处理的神经元中Cdc 25和Cdk的激活。类似地，Cdc 25同种型在Cdk 5位点的磷酸化抗性突变体在A β（1-42）处理的初级皮质神经元中激活Cdk 1、Cdk 2和Cdk 4是有缺陷的，强调了Cdk 5在AD发病机制中激活Cdc 25同种型和Cdks的主要作用。这些结果在人类AD临床样品中得到进一步证实，与年龄匹配的对照相比，人类AD临床样品具有更高的Cdc 25 A、Cdc 25 B和Cdc 25 C活性，这与增加的Cdk 5活性一致。Cdk 5的抑制赋予最高的神经保护作用，对A β（1-42）的毒性，而Cdc 25亚型的抑制是部分神经保护，进一步强调了Cdk 5失调细胞周期驱动的AD神经元死亡的决定性作用。
Aberrant activation of cell cycle proteins is believed to play a critical role in Alzheimer's disease (AD) pathogenesis; although, the molecular mechanisms leading to their activation in diseased neurons remain elusive. The goal of this study was to investigate the mechanistic link between Cdk5 deregulation and cell cycle re-activation in beta-amyloid(1-42) (A beta(1-42))-induced neurotoxicity. Using a chemical genetic approach, we identified Cdc25A, Cdc25B and Cdc25C as direct Cdk5 substrates in mouse brain lysates. We show that deregulated Cdk5 directly phosphorylates Cdc25A, Cdc25B and Cdc25C at multiple sites, which 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. Selective inhibition of Cdk5 abrogates Cdc25 and Cdk activations in A beta(1-42)-treated neurons. Similarly, phosphorylation-resistant mutants of Cdc25 isoforms at Cdk5 sites are defective in activating Cdk1, Cdk2 and Cdk4 in A beta(1-42)-treated primary cortical neurons, emphasizing a major role of Cdk5 in the activation of Cdc25 isoforms and Cdks in AD pathogenesis. These results were further confirmed in human AD clinical samples, which had higher Cdc25A, Cdc25B and Cdc25C activities that were coincident with increased Cdk5 activity, as compared to age-matched controls. Inhibition of Cdk5 confers the highest neuroprotection against A beta(1-42) toxicity, whereas inhibition of Cdc25 isoforms was partially neuroprotective, further emphasizing a decisive role of Cdk5 deregulation in cell-cycle-driven AD neuronal death.