Proteomic analysis of neonatal mouse brain: Evidence for hypoxia- and ischemia-induced dephosphorylation of collapsin response mediator proteins
Proteomic analysis of neonatal mouse brain: Evidence for hypoxia- and ischemia-induced dephosphorylation of collapsin response mediator proteins
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DOI：
10.1021/pr800108k
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发表时间：
2008-06-01
影响因子：
4.4
通讯作者：
Chiu, Jen-Fu
中科院分区：
文献类型：
--
作者：
Zhou, Yuan;Bhatia, Inderjeet;Chiu, Jen-Fu
围产期缺氧和缺血（HI）是死亡率和发病率的重要原因。为了了解HI诱导脑损伤的分子机制，我们使用蛋白质组学方法分析了HI治疗后24小时新生小鼠大脑中蛋白质的改变和修饰。HI脑组织中坍缩反应介质蛋白（CRMPs）发生显著变化。CRMPs是参与轴突引导和神经元生长的细胞质蛋白家族。我们发现，在HI治疗后，CRMP2、CRMP4和CRMP5蛋白在翻译后发生了改变。质谱和Western blot分析检测HI后低磷酸化的CRMP蛋白。对CRMP激酶的进一步分析表明，细胞周期蛋白依赖性激酶5 （CDK5）失活，CDK5是CRMP的启动激酶，也是神经元特异性激酶，在神经元发育和存活中起关键作用。CDK5活性的降低与其激活剂p35的低表达有关。综上所述，我们的研究结果揭示了hi诱导新生儿大脑中CRMPs的去磷酸化，并提出了这种修饰的新机制。低磷酸化的CRMPs可能与hiv相关神经系统疾病的发病机制有关。
Perinatal hypoxia and ischemia (HI) are a significant cause of mortality and morbidity. To understand the molecular mechanisms for HI-induced brain damage, here we used a proteomic approach to analyze the alteration and modification of proteins in neonatal mouse brain 24 h after HI treatment. Significant changes of collapsin response mediator proteins (CRMPs) were observed in HI brain. CRMPs are a family of cytosolic proteins involved in axonal guidance and neuronal outgrowth. We found that CRMP2, CRMP4 and CRMP5 proteins were altered post-translationally after HI treatment. Mass spectrometric and Western blot analyses detected hypophosphorylated CRMP proteins after HI. Further analysis of CRMP kinases indicated inactivation of cyclin dependent kinase 5 (CDK5), a priming kinase of CRMPs and a neuronal specific kinase that plays pivotal roles in neuronal development and survival. The reduction of CDK5 activity was associated with underexpression of its activator p35. Taken together, our findings reveal HI-induced dephosphorylation of CRMPs in neonatal brain and suggest a novel mechanism for this modification. Hypophosphorylated CRMPs might be implicated in the pathogenesis of HI-related neurological disorders.