Hallows Janice L, Iosif Robert E, Biasell Rebecca D, Vincent Inez
Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
J Neurosci. 2006 Mar 8;26(10):2738-44. doi: 10.1523/JNEUROSCI.4834-05.2006.
Hyperactivation of the cyclin-dependent kinase 5 (cdk5), triggered by proteolytic conversion of its neuronal activator, p35, to a more potent byproduct, p25, has been implicated in Alzheimer's disease (AD), amyotrophic lateral sclerosis, and Niemann-Pick type C disease (NPC). This mechanism is thought to lead to the development of neuropathological hallmarks, i.e., hyperphosphorylated cytoskeletal proteins, neuronal inclusions, and neurodegeneration, that are common to all three diseases. This pathological ensemble is recapitulated in a single model, the npc-1 (npc(-/-)) mutant mouse. Previously, we showed that pharmacological cdk inhibitors dramatically reduced hyperphosphorylation, lesion formation, and locomotor defects in npc(-/-) mice, suggesting that cdk activity is required for NPC pathogenesis. Here, we used genetic ablation of the p35 gene to examine the specific involvement of p35, p25, and hence cdk5 activation in NPC neuropathogenesis. We found that lack of p35/p25 does not slow the onset or progression or improve the neuropathology of NPC. Our results provide direct evidence that p35/p25-mediated cdk5 deregulation is not essential for NPC pathology and suggest that similar pathology in AD may also be cdk5 independent.
细胞周期蛋白依赖性激酶5（cdk5）的过度激活由其神经元激活剂p35经蛋白水解转化为更具活性的副产物p25所触发，这与阿尔茨海默病（AD）、肌萎缩侧索硬化症和尼曼-匹克C型病（NPC）有关。这种机制被认为会导致神经病理学特征的发展，即所有这三种疾病共有的细胞骨架蛋白过度磷酸化、神经元包涵体和神经退行性变。在单一模型，即npc-1（npc（-/-））突变小鼠中可重现这种病理情况。此前，我们表明，药理学上的cdk抑制剂可显著降低npc（-/-）小鼠的过度磷酸化、损伤形成和运动缺陷，这表明cdk活性是NPC发病机制所必需的。在此，我们利用p35基因的基因敲除来研究p35、p25以及因此cdk5激活在NPC神经发病机制中的具体作用。我们发现，缺乏p35/p25并不会延缓NPC的发病或进展，也不会改善其神经病理学。我们的结果提供了直接证据，表明p35/p25介导的cdk5失调对NPC病理并非必不可少，并表明AD中的类似病理也可能与cdk5无关。
