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细胞周期蛋白依赖性蛋白激酶5 在中枢神经系统发育和神经退行性疾病中的作用

陈洁, 王中峰^*

复旦大学脑科学研究院，神经生物学研究所，医学神经生物学国家重点实验室，上海 200032

摘要

脯氨酸引导的丝/ 苏氨酸蛋白酶——细胞周期蛋白依赖性蛋白激酶5 (cyclin-dependent kinase 5, Cdk5)是细胞周期素依赖的蛋白酶家族中一个特殊成员。Cdk5 不参与细胞周期调控，其活化需要与神经元内广泛表达的激活因子—— p35 或p39相结合。正常情况下，Cdk5 的转录及活性受到体内相关机制的严格调控。在神经系统发育及成熟阶段，Cdk5 通过磷酸化细胞骨架蛋白、信号分子以及调节蛋白等众多底物蛋白的特异性丝/ 苏氨酸位点，在神经元的迁移分化、存活和突触的发生、信息传递、可塑性等诸多方面发挥重要的作用。此外，在一些病理条件下，p35 的病理性剪切和Cdk5/p25 的形成所导致的Cdk5 活性失调及其亚细胞分布改变则促进了神经元的凋亡或死亡，参与了阿尔茨海默氏病(Alzheimer’s disease,AD)、帕金森氏病(Parkinson’s disease, PD)、亨廷顿氏病(Huntington’s disease, HD)以及脊髓侧索硬化症(amyotrophic lateralsclerosis, ALS)等众多神经退行性疾病的发生发展过程。本文综述了Cdk5 在中枢神经系统发育和神经退行性疾病中的作用研究方面的进展。

关键词： 细胞周期蛋白依赖性蛋白激酶5 ; p35; p25; 突触传递; 突触可塑性; 神经元存活; 神经元死亡; 神经退行性疾病

分类号：R363.1+3; R363.2+1

[Roles of cyclin-dependent kinase 5 in central nervous system development and neurodegenerative diseases.] [Ariticle in Chinese]

CHEN Jie, WANG Zhong-Feng^*

Institutes of Brain Science, Institute of Neurobiology and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China

Abstract

Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase, and plays multiple roles in neuron developmentand synaptic plasticity. The active form of Cdk5 is found primarily in the central nervous system (CNS) due to its activatorproteins p35 or p39 ubiquitously expressed in neuronal cells. Normally, the transcription and activity of Cdk5 are strictly regulated byseveral ways. In the physiological condition, Cdk5 plays a key role in the CNS development by phosphorylating the specific serine orthreonine site of numerous substrate proteins that are closely associated with the neuronal migration, synaptogenesis, synaptictransmission as well as synaptic plasticity. Under pathological conditions, p35 can be truncated into p25, which can strongly andconsistently activate Cdk5, change the cellular localization of Cdk5 and lead to neuronal death ultimately. The increasing evidence hasshowed that Cdk5 is involved in the pathogenesis of many neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’sdisease, Huntington’s disease and amyotrophic lateral sclerosis etc., indicating that Cdk5 may be a potential target in the treatment ofthe neurodegenerative diseases. In this article, we reviewed the recent progress regarding the roles of Cdk5 in CNS development andneurodegenerative diseases.

Key words: cyclin-dependent kinase 5; p35; p25; synaptic transmission; synaptic plasticity; neuronal survival; neuronal death; neurodegenerative diseases

收稿日期：2010-06-30　　录用日期：2010-07-30

通讯作者：王中峰　　E-mail: zfwang@fudan.edu.cn

引用本文：

陈洁, 王中峰. 细胞周期蛋白依赖性蛋白激酶5 在中枢神经系统发育和神经退行性疾病中的作用[J]. 生理学报 2010; 62 (4): 295-308.

CHEN Jie, WANG Zhong-Feng. [Roles of cyclin-dependent kinase 5 in central nervous system development and neurodegenerative diseases.] [Ariticle in Chinese] . Acta Physiol Sin 2010; 62 (4): 295-308 (in Chinese with English abstract).