Hyperphosphorylation of RNA polymerase II and reduced neuronal RNA levels precede neurofibrillary tangles in Alzheimer disease.

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.

Mitotic activation: a convergent mechanism for a cohort of neurodegenerative diseases.

Previous evidence from our lab and others has implicated the mitotic cdc2/cyclin B1 kinase in the neurofibrillary degeneration of Alzheimer's disease. To examine the specificity of this relationship, and define conditions leading to atypical activation of mitotic kinase in postmitotic neurons, we have applied antibodies specific for the cdc2 kinase, its activator, cyclin B1, and three cdc2 produced phosphoepitopes: the TG-3 phosphoepitope in tau and nucleolin, the MPM-2 phosphoepitope in a variety of substrates, and the H5 phosphoepitope in RNA polymerase II, to affected brain regions from a spectrum of neurodegenerative disorders. Our results demonstrate that neurons containing characteristic lesions in a subset of diseases including Down Syndrome (DS), Frontotemporal Dementia linked to chromosome 17 (FTD-17), Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Parkinson-Amyotrophic Lateral Sclerosis of Guam (GP-ALS), Niemann Pick disease type C (NPDC), and Pick's disease, display mitotic indices, implicating diverse etiologies in mitotic activation. The convergence of various degenerative schemes into a unified mitotic kinase-driven pathway provides a common target for therapeutic treatment of these different disorders.