Husseman J W, Hallows J L, Bregman D B, Leverenz J B, Nochlin D, Jin L W, Vincent I
Department of Pathology and the Nathan Shock Center of Excellence for Biology of Aging, University of Washington, Seattle 98195, USA.
J Neuropathol Exp Neurol. 2001 Dec;60(12):1219-32. doi: 10.1093/jnen/60.12.1219.
Affected neurons of Alzheimer disease (AD) brain are distinguished by the presence of the cell cycle cdc2 kinase and mitotic phosphoepitopes. A significant body of previous data has documented a decrease in neuronal RNA levels and nucleolar volume in AD brain. Here we present evidence that integrates these seemingly distinct findings and offers an explanation for the degenerative outcome of the disease. During mitosis cdc2 phosphorylates and inhibits the major transcriptional regulator RNA polymerase II (RNAP II). We therefore investigated cdc2 phosphorylation of RNAP II in AD brain. Using the H5 and H14 monoclonal antibodies specific for the cdc2-phosphorylated sites in RNAP II, we found that the polymerase is highly phosphorylated in AD. Moreover, RNAP II in AD translocates from its normally nuclear compartment to the cytoplasm of affected neurons, where it colocalizes with cdc2. These M phase-like changes in RNAP II correlate with decreased levels of poly-A RNA in affected neurons. Significantly, they precede tau phosphorylation and neurofibrillary tangle formation. Our data support the hypothesis that inappropriate activation of the cell cycle cdc2 kinase in differentiated neurons contributes to neuronal dysfunction and degeneration in part by inhibiting RNAP II and cellular processes dependent on transcription.
阿尔茨海默病（AD）大脑中受影响的神经元以细胞周期蛋白依赖性激酶2（cdc2激酶）和有丝分裂磷酸表位的存在为特征。此前大量数据记录了AD大脑中神经元RNA水平和核仁体积的降低。在此，我们提供的证据整合了这些看似不同的发现，并为该疾病的退行性结局提供了解释。在有丝分裂过程中，cdc2使主要转录调节因子RNA聚合酶II（RNAP II）磷酸化并抑制其活性。因此，我们研究了AD大脑中RNAP II的cdc2磷酸化情况。使用针对RNAP II中cdc2磷酸化位点的H5和H14单克隆抗体，我们发现该聚合酶在AD中高度磷酸化。此外，AD中的RNAP II从其正常的核区室转移到受影响神经元的细胞质中，并与cdc2共定位。RNAP II的这些类似M期的变化与受影响神经元中多聚腺苷酸RNA水平的降低相关。值得注意的是，它们先于tau蛋白磷酸化和神经原纤维缠结的形成。我们的数据支持这样一种假说，即分化神经元中细胞周期cdc2激酶的不适当激活部分通过抑制RNAP II和依赖转录的细胞过程，导致神经元功能障碍和退化。
