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、运输和组装在发育和空间上受到特定激酶的调节，这些激酶广泛磷酸化不同基序，例如 NF-M 和 NF-H 羧基末端尾部结构域中的 Lys-Ser-Pro (KSP) 重复序列。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。据信细胞周期蛋白依赖性激酶 5 (Cdk5) 可以磷酸化 NF 和 tau 蛋白中的 KSP 基序。后来的磷酸化仅发生在阿尔茨海默病大脑中的 tau 蛋白中发现的相同位点。 NF 磷酸化异常也与神经退行性疾病有关。为了描述特定激酶在体内神经退行性过程中的精确作用，我们培育了 Cdk5 缺失小鼠，该小鼠表现出与皮质层状结构和小脑叶状结构缺失相关的异常皮质生成；脑干和脊髓中大运动神经元的退行性变化伴随着 NF 免疫反应性的异常积累。随后对 Cdk5 无效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 的作用受到中枢神经系统的限制。使用Cre-plox系统生成Cdk5的条件敲除小鼠。这些小鼠出生时基本正常，但表现出不寻常的姿势和运动，表明周围神经系统存在潜在异常。这些老鼠是c