Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles
Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles
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DOI：
10.1016/s0896-6273(03)00627-5
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发表时间：
2003-10-30
期刊：
影响因子：
16.2
通讯作者：
Tsai, LH
中科院分区：
文献类型：
--
作者：
Cruz, JC;Tseng, HC;Tsai, LH
细胞周期蛋白依赖性激酶5（Cdk 5）及其调节亚基p35是哺乳动物中枢神经系统正常发育中不可或缺的参与者。p35的蛋白水解切割产生p25，导致异常Cdk 5活化。p25的积累与几种神经退行性疾病有关。在原代神经元中，p25导致细胞凋亡和tau蛋白过度磷酸化。然而，目前表达p25的小鼠模型未能在体内严格重现这些表型。在这里，我们产生了诱导型转基因小鼠线过表达p25在出生后的前脑。p25的诱导优先将Cdk 5导向病理底物。这些动物在皮质和海马中表现出神经元损失，伴有前脑萎缩、星形胶质细胞增生和caspase-3激活。内源性tau蛋白在许多表位过度磷酸化，聚集的tau蛋白积累，神经病理学在这些动物中逐渐发展。我们的累积研究结果提供了令人信服的证据，在体内失调的Cdk 5的p25神经退行性变和神经病理学的发展中起着致病作用。
Cyclin-dependent kinase 5 (Cdk5) and its regulatory subunit p35 are integral players in the proper development of the mammalian central nervous system. Proteolytic cleavage of p35 generates p25, leading to aberrant Cdk5 activation. The accumulation of p25 is implicated in several neurodegenerative diseases. In primary neurons, p25 causes apoptosis and tau hyperphosphorylation. Current mouse models expressing p25, however, fail to rigorously recapitulate these phenotypes in vivo. Here, we generated inducible transgenic mouse lines overexpressing p25 in the postnatal forebrain. Induction of p25 preferentially directed Cdk5 to pathological substrates. These animals exhibited neuronal loss in the cortex and hippocampus, accompanied by forebrain atrophy, astrogliosis, and caspase-3 activation. Endogenous tau was hyperphosphorylated at many epitopes, aggregated tau accumulated, and neurofibrillary pathology developed progressively in these animals. Our cumulative findings provide compelling evidence that in vivo deregulation of Cdk5 by p25 plays a causative role in neurodegeneration and the development of neurofibrillary pathology.