Novel control of CDK5 function in the brain

 描述(申请人提供)：细胞周期蛋白依赖的激酶5(CDK5)是一个关键的角色，它通过不同蛋白质靶点上的丝氨酸和苏氨酸残基的磷酸化来调控大脑的发育和功能。与其他CDK成员不同，CDK5不控制正常的细胞周期进程，但在有丝分裂后脑神经元中控制神经元迁移、树突棘密度、神经递质受体信号转导和活性依赖的突触可塑性方面发挥着重要作用。此外，据报道，CDK5的调节失调出现在越来越多的脑部疾病中，包括阿尔茨海默病、精神分裂症、中风和癫痫。CDK5的激活取决于CDK5R1和CDK5R2基因编码的两个非周期蛋白激活剂p35或P39的可获得量。以往的研究主要集中在p35在控制CDK5信号转导中的作用，部分原因是p35-/-小鼠在胚胎脑发育中的严重表型，以及p35参与神经毒性损伤。为什么出生后的脑神经元表达丰富的P39尚不清楚，而且不幸的是研究不足。重要的是，新出现的证据已经揭示了p35和p39在正常和疾病大脑中的不同功能。然而，调控神经元中CDK5激活剂表达的分子机制，进而控制CDK5的活性，目前还知之甚少。特别是，哪个CDK5激活剂负责调节CDK5的活性并促进神经元和突触的发育还没有确定。此外，神经元激活是否以及如何调节CDK5激活剂的表达从而支持CDK5依赖的脑功能是一个有趣的问题，仍有待回答。这项建议的重点是阐明编码P39的CDK5R2基因的调控和功能。根据我们的初步数据，我们假设在神经元分化和激活过程中，P39的选择性调节负责调节CDK5的活性，从而将CDK5信号导向特定的靶点，以控制突触的发育和脑功能，以响应生理和病理的挑战。我们提出以下具体目标来验证这一假说：(1)确定在神经元发育过程中调节P39表达的分子机制；(2)确定P39在CDK5信号和树突棘/突触发育中的功能和靶点；(3)确定P39在学习记忆形成和癫痫发生中的作用。

 DESCRIPTION (provided by applicant): Cyclin-dependent kinase 5 (CDK5) is a key player that governs brain development and function by phosphorylation of serine and threonine residues on diverse protein targets. Unlike other CDK members, CDK5 does not control normal cell cycle progression, but plays prominent roles in controlling neuronal migration, dendritic spine density, neurotransmitter receptor signaling, and activity-dependent synaptic plasticity in post-mitotic brain neurons. Moreover, dysregulation of CDK5 is reported in an increasing list of brain disorders, including Alzheimer's disease, schizophrenia, stroke, and epilepsy. Activation of CDK5 depends on the available amount of p35 or p39, two non-cyclin activators encoded by the CDK5R1 and CDK5R2 gene, respectively. Previous studies have overwhelmingly focused on the function of p35 in controlling CDK5 signaling, partly due to the severe phenotype of p35-/- mice in embryonic brain development and the involvement of p35 in neurotoxic damage. Why postnatal brain neurons express abundant p39 is not understood and unfortunately understudied. Importantly, emerging evidence has revealed differential functions of p35 and p39 in normal and diseased brains. However, molecular mechanisms that regulate CDK5 activator expression in neurons, which in turn govern CDK5 activity, are vastly unknown. In particular, which CDK5 activator is responsible for modulating CDK5 activity and promoting neuronal and synapse development is undefined. Moreover, whether and how neuronal activation regulates CDK5 activator expression thus underlie CDK5-dependent brain function is an intriguing question that remains to be answered. This proposal focuses on elucidating the regulation and function of the CDK5R2 gene that encodes p39. Based on our preliminary data, we hypothesize that selective regulation of p39 is responsible for modulating CDK5 activity during neuronal differentiation and activation, which directs CDK5 signaling toward specific targets to control synaptic development and brain function in response to physiological and pathological challenges. We propose the following Specific Aims to test this hypothesis: (1) To determine molecular mechanisms that regulate p39 expression during neuronal development and in response to neuronal activity changes; (2) to determine the function and targets of p39 in CDK5 signaling and dendritic spine/synapse development; (3) To determine the role of p39 in learning and memory formation and epileptogenesis.