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重要作用。神经丝（NF）蛋白的合成，转运和组装在发育和空间上受到特定激酶的调节，这些激酶会在NF- M和NF-H的羧基末端尾域中广泛磷酸化的不同基序（例如裂解词）重复。这种磷酸化稳定了轴突中的NF网络，并影响神经元中的轴突运输和传导速度。据信Cyclin依赖性激酶5（CDK5）在NF和Tau蛋白中磷酸化KSP基序。后来的磷酸化仅发生在阿尔茨海默氏病大脑的tau蛋白中的相同部位。 NF异常的NF磷酸化也已与神经变性疾病有关。为了描述特定激酶在体内神经脱生过程中的精确作用，我们产生了CDK5无效小鼠，该小鼠表现出异常的皮质生成，与缺乏皮质层状结构和小脑叶状相关。 NF免疫反应性异常积累的大型运动神经元和脊髓中的大型运动神经元的退化变化。随后对CDK5 NULL表型的分析揭示了一种新的细胞自主途径，CDK5通过该途径对神经元迁移和皮质生成发挥作用。我们最近的研究表明CDK5的CNS限制性作用。使用CRE-Plox系统生成了用于CDK5的条件敲除小鼠。这些小鼠在出生时严重正常，但表现出异常的姿势和运动，表明周围神经系统中潜在的异常。这些小鼠是C