Cytoplasmic ATM in neurons modulates synaptic function

Curr Biol. 2009 Dec 29;19(24):2091-6. doi: 10.1016/j.cub.2009.10.039. Epub 2009 Dec 3.

Abstract

ATM is a PI 3-kinase involved in DNA double-strand break repair. ATM deficiency leads to ataxia-telangiectasia (A-T), a syndrome of cancer susceptibility, hypersensitivity to ionizing radiation, immune deficiency, and sterility [1, 2]-phenotypes that can straightforwardly be attributed to a defective response to DNA damage. Yet patients with A-T also suffer from ataxia, speech defects, and abnormal body movements [3-5]-neurological phenotypes whose origins remain largely unexplained. Compounding the discordance, Atm mutations in mouse interfere with DNA repair but have only mild neurological symptoms [6-9], suggesting that the link between DNA damage and the death of neurons can be broken [10-12]. We find that in neurons, ATM protein has a substantial cytoplasmic distribution. We show that in Atm(tm1Awb) mice, hippocampal long-term potentiation is significantly reduced, as is the rate of spontaneous vesicular dye release, suggesting a functional importance of cytoplasmic ATM. In the cytoplasm, ATM forms a complex with two synaptic vesicle proteins, VAMP2 and synapsin-I, both of which must be phosphorylated to bind ATM. Also, cytoplasmic ATM physically associates with the homologous PI 3-kinase, ATR. The neurological symptoms of ataxia-telangiectasia may thus result from defective nonnuclear functions of ATM not associated with DNA repair.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia / metabolism*
  • Ataxia Telangiectasia / pathology
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism*
  • Cytoplasm / enzymology*
  • DNA Damage / physiology*
  • DNA-Binding Proteins / metabolism*
  • Excitatory Postsynaptic Potentials
  • Hippocampus / physiology*
  • Long-Term Potentiation
  • Mice
  • Microscopy, Fluorescence
  • Neurons / enzymology*
  • Phosphorylation
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA, Small Interfering / genetics
  • Synapses / physiology*
  • Synapsins / metabolism
  • Tumor Suppressor Proteins / metabolism*
  • Vesicle-Associated Membrane Protein 2 / metabolism

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • RNA, Small Interfering
  • Synapsins
  • Tumor Suppressor Proteins
  • Vesicle-Associated Membrane Protein 2
  • vesicle-associated membrane protein 2, mouse
  • Atr protein, mouse
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein Serine-Threonine Kinases