Hippocampal neurons of mice deficient in DNA-dependent protein kinase exhibit increased vulnerability to DNA damage, oxidative stress and excitotoxicity.
DNA damage has been documented in neurodegenerative conditions ranging from Alzheimer's disease to stroke. DNA-dependent protein kinase (DNA-PK) is involved in V(D)J recombination and DNA double strand break repair, and may play a role in cell death induced by DNA damage. We now report that cultured hippocampal neurons from severe combined immunodeficient (scid) mice which lack DNA-PK activity are hypersensitive to apoptosis induced by exposure to topoisomerase inhibitors, amyloid beta peptide (A beta) and glutamate. A similar increased vulnerability of hippocampal CA1 and CA3 neurons was observed in adult scid mice after kainate-induced seizures. Our results suggest that DNA-PK activity is important for neuron survival under conditions that may occur in neurological disorders.
Culmsee
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Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Bondada
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Mattson
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D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D002166:Camptothecin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004827:Epilepsy / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology*; D051379:Mice; D016513:Mice, SCID; D009474:Neurons / Q000201:enzymology*; D009498:Neurotoxins / Q000494:pharmacology*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency*; D059004:Topoisomerase I Inhibitors
D016229:Amyloid beta-Peptides; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009498:Neurotoxins; D019384:Nucleic Acid Synthesis Inhibitors; D059004:Topoisomerase I Inhibitors; D018698:Glutamic Acid; D005047:Etoposide; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases; D002166:Camptothecin