CDK5 ACTIVATORS IN NEURITE POLARIZATION AND DEGENERATION

描述(由申请人提供) 细胞周期蛋白依赖性激酶5(CDK5)是一种小的丝氨酸-苏氨酸激酶 对于哺乳动物神经系统的正常发育和异常激活 参与了细胞骨架异常的发病机制 以及神经退行性疾病中的神经元死亡。要被激活，CDK5必须 与调控亚单位相关联，如P35或P39。该系统的实验 本提案旨在对这两个人的参与进行高度分析 神经元极化和B-淀粉样蛋白诱导的相关CDK5激活剂 神经退行性变。需要检验的具体假设是：1)p35和 P39具有不同的表达模式和亚细胞定位、靶向性 CDK5与不同的底物结合，因此在 神经元发育。在这方面，我们特别建议p35是 主要参与轴突过程中细胞骨架动力学的调节 P39参与突触形成；2)MAPK通路激活 通过细胞外基质分子，如层粘连蛋白，或由B-淀粉样蛋白增强 CDK5的活性通过促进p35和/或p39的合成来实现。这些实验 将利用培养的海马体锥体作为模型系统进行实验 细胞和分子生物学中的几种最新技术。这个 我们期望取得的结果肯定会有助于更好地 了解神经突起极化和分化的机制 中枢神经元变性。

DESCRIPTION (provided by applicant) Cyclin-dependent kinase 5 (Cdk5), a small serine-threonine kinase is required for proper development of the mammalian nervous system, and abnormal activation of this kinase is involved in the pathogenesis of cytoskeletal abnormalities and neuronal death in neurodegenerative disorders. To be activated, Cdk5 has to associate with regulatory subunits, such as p35 or p39. The experiments of the present proposal are directed to analyze the participation of these two highly related Cdk5 activators in neuronal polarization and in B-amyloid induced neurodegeneration. The specific hypotheses to be tested are that: 1) p35 and p39 have different expression patterns and subcellular localization, targeting Cdk5 to different substrates and hence having different functional roles during neuronal development. In this regard, we specifically propose that p35 is mainly involved in the regulation of cytoskeletal dynamics during axon formation, while p39 in synaptogenesis; and 2) Activation of the MAPK pathway by extracellular matrix molecules, such as laminin, or by B-amyloid enhances Cdk5 activity by promoting the synthesis of p35 and/or p39. These experiments will be carried out using as a model system cultured hippocampal pyramidal and several state of the art techniques in cellular and molecular biology. The results that we expect to obtain will certainly contribute to a better understanding of the mechanisms underlying neurite polarization and degeneration in central neurons.