Cytoplasmic ATM in neurons modulates synaptic function.
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.
Li
Jiali
J
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
Han
Yu R
YR
Plummer
Mark R
MR
Herrup
Karl
K
D000818:Animals; D001260:Ataxia Telangiectasia / Q000378:metabolism* / Q000473:pathology; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D003593:Cytoplasm / Q000201:enzymology*; D004249:DNA Damage / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials; D006624:Hippocampus / Q000502:physiology*; D017774:Long-Term Potentiation; D051379:Mice; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000201:enzymology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D013569:Synapses / Q000502:physiology*; D016704:Synapsins / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D050988:Vesicle-Associated Membrane Protein 2 / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D016704:Synapsins; D025521:Tumor Suppressor Proteins; D050988:Vesicle-Associated Membrane Protein 2; C494808:vesicle-associated membrane protein 2, mouse; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases