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首页> 外文期刊>Neuron >Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles.
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Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles.

机译：p25异常激活Cdk5会触发导致神经变性和神经原纤维缠结的病理事件。

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摘要

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.
机译：细胞周期蛋白依赖性激酶5（Cdk5）及其调节亚基p35在哺乳动物中枢神经系统的正常发育中起着不可或缺的作用。 p35的蛋白水解切割产生p25，导致Cdk5异常激活。 p25的积累与几种神经退行性疾病有关。在原代神经元中，p25导致凋亡和tau过度磷酸化。但是，目前表达p25的小鼠模型无法在体内严格概括这些表型。在这里，我们生成了在产后前脑中过表达p25的诱导型转基因小鼠品系。 p25的诱导优先将Cdk5定向到病理底物。这些动物在皮质和海马中表现出神经元丢失，伴有前脑萎缩，星形胶质增生和caspase-3活化。内源性tau在许多表位上都被过度磷酸化，聚集了tau并在这些动物中逐渐发展出神经原纤维病理。我们的累积发现提供了令人信服的证据，表明p25在体内对Cdk5的失控在神经变性和神经原纤维病理学发展中起着致病作用。

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