1. Deregulation of HDAC1 by p25/Cdk5 in Neurotoxicity
- Author
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Christopher Lee Frank, Nisha Broodie, Weihong Tu, Ji-Song Guan, Paola Giusti, Stephen J. Haggarty, Youming Lu, Rachel K. Tsunemoto, Matthew M. Dobbin, Peter L. Peng, Li-Huei Tsai, Lily Y. Moy, Byung-Hoon Lee, Ivanna Delalle, Ralph Mazitschek, Rachael L. Neve, and Dohoon Kim
- Subjects
HUMDISEASE ,Gene Expression ,Histone Deacetylase 1 ,Mice ,0302 clinical medicine ,Ischemia ,Conditioning, Psychological ,DNA Breaks, Double-Stranded ,Nerve Tissue ,Cells, Cultured ,Cerebral Cortex ,Neurons ,0303 health sciences ,General Neuroscience ,Neurodegeneration ,Cell Cycle ,Fear ,Cell cycle ,3. Good health ,Cell biology ,SIGNALING ,Comet Assay ,Chromatin Immunoprecipitation ,DNA damage ,Neuroscience(all) ,Green Fluorescent Proteins ,Mice, Transgenic ,Biology ,Transfection ,MOLNEURO ,Histone Deacetylases ,03 medical and health sciences ,Prosencephalon ,Proliferating Cell Nuclear Antigen ,medicine ,Animals ,Humans ,030304 developmental biology ,Gene Expression Profiling ,Neurotoxicity ,Cyclin-Dependent Kinase 5 ,medicine.disease ,HDAC1 ,Proliferating cell nuclear antigen ,Rats ,Comet assay ,Mice, Inbred C57BL ,Ki-67 Antigen ,nervous system ,Animals, Newborn ,Chromobox Protein Homolog 5 ,Nerve Degeneration ,biology.protein ,Chromatin immunoprecipitation ,030217 neurology & neurosurgery ,DNA Damage - Abstract
Summary Aberrant cell-cycle activity and DNA damage are emerging as important pathological components in various neurodegenerative conditions. However, their underlying mechanisms are poorly understood. Here, we show that deregulation of histone deacetylase 1 (HDAC1) activity by p25/Cdk5 induces aberrant cell-cycle activity and double-strand DNA breaks leading to neurotoxicity. In a transgenic model for neurodegeneration, p25/Cdk5 activity elicited cell-cycle activity and double-strand DNA breaks that preceded neuronal death. Inhibition of HDAC1 activity by p25/Cdk5 was identified as an underlying mechanism for these events, and HDAC1 gain of function provided potent protection against DNA damage and neurotoxicity in cultured neurons and an in vivo model for ischemia. Our findings outline a pathological signaling pathway illustrating the importance of maintaining HDAC1 activity in the adult neuron. This pathway constitutes a molecular link between aberrant cell-cycle activity and DNA damage and is a potential target for therapeutics against diseases and conditions involving neuronal death.
- Published
- 2008
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