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（NF）蛋白的合成、转运和组装在发育和空间上由特异性激酶调节，所述激酶广泛磷酸化不同基序，例如NF-M和NF-H的羧基末端尾结构域中的Lys-Ser-Pro（KSP）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。细胞周期蛋白依赖性激酶-5（Cdk 5）被认为磷酸化NF和tau蛋白中的KSP基序。后来的磷酸化只发生在相同的网站上发现的tau蛋白从阿尔茨海默氏症？疾病的大脑。异常的NF磷酸化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确切作用，我们产生了Cdk 5基因敲除小鼠，其表现出与皮质层状结构和小脑叶状结构的缺失相关的异常皮质生成;脑干和脊髓中的大运动神经元的退行性变化以及NF免疫反应性的异常积累。随后对Cdk 5空表型的分析揭示了一种新的细胞自主途径，Cdk 5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，CNS限制的Cdk 5的作用。采用Cre-plox系统建立Cdk 5条件性基因敲除小鼠。这些小鼠出生时大体正常，但表现出异常的姿势和运动，表明周围神经系统可能异常。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