PHOSPHORYLATION OF NEURONAL CYTOSKELETON IN NEURODEGENERATIVE DISEASES

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。神经丝蛋白的合成、运输和组装在发育和空间上受特定的蛋白激酶的调节，这些蛋白广泛地磷酸化不同的基序，如在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中的神经营养因子网络，并影响了神经元的轴突运输和传导速度。细胞周期蛋白依赖性激酶-5(CDK5)被认为能磷酸化NF和tau蛋白中的KSP基序。后者的磷酸化仅发生在阿尔茨海默病-S病脑中发现的tau蛋白中的相同位置。神经营养因子的异常磷酸化也与神经退行性疾病有关。为了阐明特定的蛋白激酶在体内神经退行性变过程中的确切作用，我们产生了CDK5基因缺失的小鼠，它表现出皮质发育异常，皮质板层结构缺失和小脑叶片化；脑干和脊髓中的大运动神经元变性改变，伴随着NF免疫反应的异常聚集。随后对CDK5缺失表型的分析揭示了一条新的细胞自主途径，通过该途径，CDK5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的作用受到中枢的限制。用Cre-plox系统建立CDK5条件性基因敲除小鼠。这些小鼠出生时基本正常，但表现出不寻常的姿势和动作，表明周围神经系统可能出现异常。这些老鼠是c

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