Hippocampal neurons of mice deficient in DNA-dependent protein kinase exhibit increased vulnerability to DNA damage, oxidative stress and excitotoxicity

Brain Res Mol Brain Res. 2001 Mar 5;87(2):257-62. doi: 10.1016/s0169-328x(01)00008-0.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / pharmacology
  • Animals
  • Camptothecin / pharmacology
  • DNA Damage / drug effects
  • DNA Damage / physiology*
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins*
  • Enzyme Inhibitors / pharmacology
  • Epilepsy / metabolism
  • Etoposide / pharmacology
  • Glutamic Acid / pharmacology
  • Hippocampus / cytology*
  • Mice
  • Mice, SCID
  • Neurons / enzymology*
  • Neurotoxins / pharmacology*
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • Oxidative Stress / physiology
  • Protein-Serine-Threonine Kinases / deficiency*
  • Topoisomerase I Inhibitors

Substances

  • Amyloid beta-Peptides
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Neurotoxins
  • Nucleic Acid Synthesis Inhibitors
  • Topoisomerase I Inhibitors
  • Glutamic Acid
  • Etoposide
  • DNA-Activated Protein Kinase
  • Protein-Serine-Threonine Kinases
  • Camptothecin