CDK5 Contributes to Neuronal Apoptosis via Promoting MEF2D Phosphorylation in Rat Model of Intracerebral Hemorrhage
CDK5 Contributes to Neuronal Apoptosis via Promoting MEF2D Phosphorylation in Rat Model of Intracerebral Hemorrhage
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CDK5 通过促进脑出血大鼠模型中 MEF2D 磷酸化促进神经元凋亡
DOI：
10.1007/s12031-014-0466-5
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发表时间：
2015-05-01
影响因子：
3.1
通讯作者：
Liu, Yonghua
中科院分区：
文献类型：
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作者：
Ke, Kaifu;Shen, Jiabing;Liu, Yonghua
细胞周期蛋白依赖性激酶 5 (CDK5) 是一种丝氨酸/苏氨酸激酶，可被其神经元特异性激活剂 p35 或其截短形式 p25 激活，在多种神经元事件中发挥重要作用，包括神经元迁移、突触传递和神经元死亡。越来越多的证据表明，CDK5 的异常激活是中枢神经系统 (CNS) 疾病中关键的神经元促死亡信号。然而，目前尚不清楚CDK5如何在脑出血（ICH）后神经元凋亡中发挥作用。在本研究中，我们通过将自体全血注射到成年大鼠的右侧基底节中来建立ICH模型，并通过行为测试评估其神经功能缺损。 ICH后血肿附近的CDK5蛋白水平和激酶活性上调。免疫荧光染色显示CDK5主要定位于神经元，而不是星形胶质细胞或少突胶质细胞。此外，活性 caspase-3（一种凋亡标记物）在 ICH 后表现出与 CDK5 的蛋白水平/激酶活性在时间上平行的表达。同时，肌细胞增强因子 2D (MEF2D)（一种可被 CDK5 磷酸化失活的促存活转录因子）在 ICH 后也表现出高磷酸化水平。在体外，我们在凝血酶处理后获得了原代皮质神经元中 CDK5 激酶活性的一致上调。降低 CDK5 激酶活性可抑制神经元凋亡，并减少 MEF2D ser444 残基的磷酸化。因此，我们推测CDK5可能在ICH后神经元凋亡的调节中发挥重要作用。
Cyclin-dependent kinase-5 (CDK5), a serine/threonine kinase which can be activated by its neuron-specific activator p35, or its truncated form p25, plays an important role in a variety of neuronal events, including neuronal migration, synaptic transmission, and neuronal death. Accumulating evidence has shown that abnormal activation of CDK5 was a critical neuronal pro-death signal in central nervous system (CNS) diseases. However, it remains unclear how CDK5 functions upon neuronal apoptosis following intracerebral hemorrhage (ICH). In the present study, we established ICH models by injecting autologous whole blood into the right basal ganglia of adult rats and assessed their neurological deficits by behavioral tests. CDK5 protein levels and kinase activities were upregulated adjacent to the hematoma following ICH. Immunofluorescent staining showed CDK5 was mainly localized in neurons, rather than in astrocytes or oligodendrocytes. Furthermore, active caspase-3, an apoptotic marker, showed a temporally parallel expression with the protein levels/kinase activities of CDK5 following ICH. Meantime, myocyte enhancer factor 2D (MEF2D), a pro-survival transcription factor which could be phosphorylated inactivation by CDK5, also exhibited high phosphorylation levels following ICH. In vitro, we obtained a consistent upregulation of CDK5 kinase activity in primary cortical neurons after thrombin treatment. Knocking down CDK5 kinase activity suppressed neuronal apoptosis and coupled with reduced MEF2D phosphorylation at ser444residues. Thus, we speculated that CDK5 might exert an important function in the regulation of neuronal apoptosis following ICH.