PHOSPHORYLATION OF NEURONAL CYTOSKELETON IN NEURODEGENERATIVE DISEASES

神经退行性疾病中神经细胞骨架的磷酸化

• 批准号: 6289701
• 负责人: Ashok B. KULKARNI
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6289701
• 关键词: cell cycle proteins; cyclin dependent kinase; cytoskeleton; developmental neurobiology; enzyme activity; enzyme induction /repression; gene targeting; laboratory mouse; neurofilament proteins; phosphorylation

Phosphorylation process plays an important role in the structural organization of neuronal cytoskeleton. Synthesis, transport and assembly of neurofilament (NF) proteins are developmentally and spatially regulated by specific kinases that extensively phosphorylate different motifs such as Lys- Ser-Pro (KSP) repeats in the carboxyl-terminal tail domain of NF- M and NF-H. This phosphorylation stabilizes the NF network in the axon, and to affect the axonal transport and conduction velocity in the neurons. Cyclin dependent kinase-5 (Cdk5) is believed to phosphorylate KSP motifs in NF and tau protein. The later phosphorylation occurs exclusively at the same sites found in the tau protein from Alzheimer?s disease brain. Abnormal NF phosphorylation has also been associated with neuro-degenerative diseases. In order to delineate precise roles of specific kinases in neuro-degenerative process in vivo, we generated Cdk5 null mouse which exhibited abnormal corticogenesis associated with absence of cortical laminar structures and cerebellar foliation; degenrative changes in the large motor neurons in the brain stem and in the spinal cord with the abnormal accumulation of NF immunoreactivity. Subsequent analysis of Cdk5 null phenotype revealed a new cell-autonomous pathway through which Cdk5 exerts its effects on the neuronal migration and corticogenesis. Our recent studies indicate CNS-restricted role for Cdk5. The conditional knockout mice for Cdk5 were generated using Cre-plox system. These mice are grossly normal at birth, but exhibit unusual postures and movements indicating potential abnormalities in the peripheral nervous system. These mice are c

磷酸化过程在神经元细胞骨架的结构组织中起着重要作用。神经丝（NF）蛋白的合成、运输和组装受到特定激酶的发育和空间调控，这些激酶广泛磷酸化不同的基序，如NF- M和NF- h的羧基末端尾部区域的Lys- Ser-Pro （KSP）重复序列。这种磷酸化稳定了轴突内的NF网络，并影响神经元内轴突的运输和传导速度。细胞周期蛋白依赖性激酶-5 （Cdk5）被认为可以磷酸化NF和tau蛋白中的KSP基序。后来的磷酸化只发生在与阿尔茨海默病的tau蛋白相同的位点上。S病大脑。异常的NF磷酸化也与神经退行性疾病有关。为了准确描述特定激酶在体内神经退行性过程中的作用，我们产生了Cdk5缺失小鼠，这些小鼠表现出与皮质层状结构缺失和小脑叶状结构缺失相关的皮质生成异常；脑干和脊髓大运动神经元的退行性改变伴NF免疫反应性异常积累。随后对Cdk5空表型的分析揭示了Cdk5在神经元迁移和皮质发生中发挥作用的一个新的细胞自主途径。我们最近的研究表明Cdk5在中枢神经系统中的作用受到限制。采用Cre-plox系统制备Cdk5条件敲除小鼠。这些小鼠在出生时非常正常，但表现出不寻常的姿势和运动，表明周围神经系统可能存在异常。这些老鼠是c