Cyclin-dependent kinase inhibitors attenuate protein hyperphosphorylation, cytoskeletal lesion formation, and motor defects in Niemann-Pick type C mice
Cyclin-dependent kinase inhibitors attenuate protein hyperphosphorylation, cytoskeletal lesion formation, and motor defects in Niemann-Pick type C mice
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DOI：
10.1016/s0002-9440(10)63347-0
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发表时间：
2004-09-01
影响因子：
6
通讯作者：
Vincent, I
中科院分区：
文献类型：
--
作者：
Zhang, M;Li, J;Vincent, I
细胞周期蛋白依赖性激酶（cdks）和细胞骨架蛋白过度磷酸化的失调表征人类神经退行性疾病的子集，包括阿尔茨海默病、肌萎缩性侧索硬化和尼曼-匹克C型（NPC）。据认为，这些细胞骨架的变化最终导致发展的标志性细胞骨架病变，如神经纤维缠结和轴突球体。虽然许多研究支持cdk参与这些神经退行性级联反应，但不知道cdk活性是否是必需的。自然发生的npc-1突变小鼠模仿人NPC，表现为cdk 5、有丝分裂cdc 2和cdk 4的激活，伴随细胞骨架病理学和神经变性。我们利用这种模型和特异性的cdk活性的药理学抑制剂，以确定cdk是否是NPC神经病理学所必需的。抑制剂注入脑室内2周的时间，开始在病理学初期阶段。虽然非活性的立体异构体，异奥洛莫辛，是无效的，两个有效的抑制剂，roscovitine和奥洛莫辛，衰减显着的神经丝，tau蛋白和有丝分裂蛋白的过度磷酸化，减少球体的数量，调制浦肯野神经元死亡，并改善运动缺陷的npc小鼠。这些结果表明，cdk活性所需的神经病理和随后的运动障碍在鼻咽癌。旨在敲除这些小鼠中的单个cdk的研究将有助于确定特定的cdk（s）是必不可少的，并描述它们在神经退行性过程中的确切作用。
Dysregulation of cyclin-dependent kinases (cdks) and cytoskeletal protein hyperphosphorylation characterizes a subset of human neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, and Niemann-Pick Type C (NPC). It is thought that these cytoskeletal changes lead eventually to development of hallmark cytoskeletal lesions such as neurofibrillary tangles and axonal spheroids. Although many studies support an involvement of cdks in these neurodegenerative cascades, it is not known whether cdk activity is essential. The naturally occurring npc-1 mutant mouse mimics human NPC, in displaying activation of cdk5, mitotic cdc2, and cdk4, with concomitant cytoskeletal pathology and neurodegeneration. We availed of this model and specific pharmacological inhibitors of cdk activity, to determine whether cdks are necessary for NPC neuropathology. The inhibitors were infused intracerebroventricularly for a 2-week period, initiated at a pathologically incipient stage. While an inactive stereoisomer, iso-olomoucine, was ineffective, two potent inhibitors, roscovitine and olomoucine, attenuated significantly the hyperphosphorylation of neurofilament, tau, and mitotic proteins, reduced the number of spheroids, modulated Purkinje neuron death, and ameliorated motor defects in npc Mice. These results suggest that cdk activity is required for neuropathology and subsequent motor impairment in NPC. Studies aimed at knocking down individual cdks in these mice will help identify the specific cdk(s) that are essential, and delineate their precise roles in the neurodegenerative process.