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Cerebral Cortex Advance Access originally published online on September 26, 2008
Cerebral Cortex 2009 19(6):1273-1293; doi:10.1093/cercor/bhn167
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© The Author 2008. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Molecular Regulation of DNA Damage-Induced Apoptosis in Neurons of Cerebral Cortex

Lee J. Martin1,2, Zhiping Liu1, Jacqueline Pipino1, Barry Chestnut1 and Melissa A. Landek1

1 Departments of Pathology, Division of Neuropathology, 2 Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Address correspondence to Dr Lee J. Martin, Johns Hopkins University School of Medicine, Department of Pathology, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA. Email: martinl{at}jhmi.edu.

Cerebral cortical neuron degeneration occurs in brain disorders manifesting throughout life, but the mechanisms are understood poorly. We used cultured embryonic mouse cortical neurons and an in vivo mouse model to study mechanisms of DNA damaged-induced apoptosis in immature and differentiated neurons. p53 drives apoptosis of immature and differentiated cortical neurons through its rapid and prominent activation stimulated by DNA strand breaks induced by topoisomerase-I and -II inhibition. Blocking p53-DNA transactivation with {alpha}-pifithrin protects immature neurons; blocking p53-mitochondrial functions with µ-pifithrin protects differentiated neurons. Mitochondrial death proteins are upregulated in apoptotic immature and differentiated neurons and have nonredundant proapoptotic functions; Bak is more dominant than Bax in differentiated neurons. p53 phosphorylation is mediated by ataxia telangiectasia mutated (ATM) kinase. ATM inactivation is antiapoptotic, particularly in differentiated neurons, whereas inhibition of c-Abl protects immature neurons but not differentiated neurons. Cell death protein expression patterns in mouse forebrain are mostly similar to cultured neurons. DNA damage induces prominent p53 activation and apoptosis in cerebral cortex in vivo. Thus, DNA strand breaks in cortical neurons induce rapid p53-mediated apoptosis through actions of upstream ATM and c-Abl kinases and downstream mitochondrial death proteins. This molecular network operates through variations depending on neuron maturity.

Key Words: Alzheimer's disease • ATM • neonatal brain injury • p53 • Parkinson's disease • stroke


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