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Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia

Molecular Psychiatry volume 12, pages 74–86 (2007)Cite this article

Abstract

Disrupted in Schizophrenia 1 (DISC1) is a schizophrenia risk gene associated with cognitive deficits in both schizophrenics and the normal ageing population. In this study, we have generated a network of protein–protein interactions (PPIs) around DISC1. This has been achieved by utilising iterative yeast-two hybrid (Y2H) screens, combined with detailed pathway and functional analysis. This so-called ‘DISC1 interactome’ contains many novel PPIs and provides a molecular framework to explore the function of DISC1. The network implicates DISC1 in processes of cytoskeletal stability and organisation, intracellular transport and cell-cycle/division. In particular, DISC1 looks to have a PPI profile consistent with that of an essential synaptic protein, which fits well with the underlying molecular pathology observed at the synaptic level and the cognitive deficits seen behaviourally in schizophrenics. Utilising a similar approach with dysbindin (DTNBP1), a second schizophrenia risk gene, we show that dysbindin and DISC1 share common PPIs suggesting they may affect common biological processes and that the function of schizophrenia risk genes may converge.

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References

  1. Tamminga CA, Holcomb HH . Phenotype of schizophrenia: a review and formulation. Mol Psychiatry 2005; 10: 27–39.

    Article  CAS  Google Scholar 

  2. Harrison PJ, Weinberger DR . Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2004; 20: 40–68.

    Google Scholar 

  3. Glantz LA, Lewis DA . Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry 2000; 57: 65–73.

    Article  CAS  Google Scholar 

  4. Krystal JH, D'Souza DC, Mathalon D, Perry E, Belger A, Hoffman R . NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology (Berl) 2003; 169: 215–233.

    Article  CAS  Google Scholar 

  5. Benes FM, Majocha R, Bird ED, Marotta CA . Increased vertical axon numbers in cingulate cortex of schizophrenics. Arch Gen Psychiatry 1987; 44: 1017–1021.

    Article  CAS  Google Scholar 

  6. Kovelman JA, Scheibel AB . A neurohistological correlate of schizophrenia. Biol Psychiatry 1984; 19: 1601–1621.

    PubMed  CAS  Google Scholar 

  7. Eastwood SL, Burnet PW, Harrison PJ . Altered synaptophysin expression as a marker of synaptic pathology in schizophrenia. Neuroscience 1995; 66: 309–319.

    Article  CAS  Google Scholar 

  8. Deakin JF, Simpson MD . A two-process theory of schizophrenia: evidence from studies in post-mortem brain. J Psychiatr Res 1997; 31: 277–295.

    Article  CAS  Google Scholar 

  9. Krystal JH, D'Souza DC, Petrakis IL, Belger A, Berman RM, Charney DS et al. NMDA agonists and antagonists as probes of glutamatergic dysfunction and pharmacotherapies in neuropsychiatric disorders. Harv Rev Psychiatry 1999; 7: 125–143.

    Article  CAS  Google Scholar 

  10. Lewis DA, Levitt P . Schizophrenia as a disorder of neurodevelopment. Annu Rev Neurosci 2002; 25: 409–432.

    Article  CAS  Google Scholar 

  11. Mohn AR, Gainetdinov RR, Caron MG, Koller BH . Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 1999; 98: 427–436.

    Article  CAS  Google Scholar 

  12. Stefani MR, Moghaddam B . Transient N-methyl-D-aspartate receptor blockade in early development causes lasting cognitive deficits relevant to schizophrenia. Biol Psychiatry 2005; 57: 433–436.

    Article  CAS  Google Scholar 

  13. Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 2000; 9: 1415–1423.

    Article  CAS  Google Scholar 

  14. Braff DL, Light GA . Preattentional and attentional cognitive deficits as targets for treating schizophrenia. Psychopharmacology (Berl) 2004; 174: 75–85.

    Article  CAS  Google Scholar 

  15. Blackwood DH, Fordyce A, Walker MT, St Clair DM, Porteous DJ, Muir WJ . Schizophrenia and affective disorders – cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet 2001; 69: 428–433.

    Article  CAS  Google Scholar 

  16. Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR et al. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci 2005; 102: 8627–8632.

    Article  CAS  Google Scholar 

  17. Brandon NJ, Handford EJ, Schurov I, Rain JC, Pelling M, Duran-Jimeniz B et al. Disrupted in schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders. Mol Cell Neurosci 2004; 25: 42–55.

    Article  CAS  Google Scholar 

  18. Morris JA, Kandpal G, Ma L, Austin CP . DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. Hum Mol Genet 2003; 12: 1591.

    Article  CAS  Google Scholar 

  19. Ozeki Y, Tomoda T, Kleiderlein J, Kamiya A, Bord L, Fujii K et al. Disrupted-in-Schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth. Proc Natl Acad Sci USA 2003; 100: 289–294.

    Article  CAS  Google Scholar 

  20. Millar JK, Pickard BS, Mackie S, James R, Christie S, Buchanan SR et al. DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science 2005; 310: 1187–1191.

    Article  CAS  Google Scholar 

  21. Arnold SE, Talbot K, Hahn CG . Neurodevelopment, neuroplasticity, and new genes for schizophrenia. Prog Brain Res 2005; 147: 319–345.

    Article  CAS  Google Scholar 

  22. Fromont-Racine M, Rain JC, Legrain P . Building protein–protein networks by two-hybrid mating strategy. Methods Enzymol 2002; 350: 513–524.

    Article  CAS  Google Scholar 

  23. Rain JC, Selig L, De Reuse H, Battaglia V, Reverdy C, Simon S et al. The protein–protein interaction map of Helicobacter pylori. Nature 2001; 409: 211–215.

    Article  CAS  Google Scholar 

  24. Huang X, Madan A . CAP3: A DNA sequence assembly program. Genome Res 1999; 9: 868–877.

    Article  CAS  Google Scholar 

  25. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ . Basic local alignment search tool. J Mol Biol 1990; 215: 403–410.

    Article  CAS  Google Scholar 

  26. Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A et al. Functional proteomics mapping of a human signaling pathway. Genome Res 2004; 14: 1324–1332.

    Article  CAS  Google Scholar 

  27. Formstecher E, Aresta S, Collura V, Hamburger A, Meil A, Trehin A et al. Protein interaction mapping: a Drosophila case study. Genome Res 2005; 15: 376–384.

    Article  CAS  Google Scholar 

  28. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 2000; 25: 25–29.

    Article  CAS  Google Scholar 

  29. Liu S, Altman RB . Large scale study of protein domain distribution in the context of alternative splicing. Nucleic Acids Res 2003; 31: 4828–4835.

    Article  CAS  Google Scholar 

  30. Mulder NJ, Apweiler R, Attwood TK, Bairoch A, Bateman A, Binns D et al. InterPro, progress and status in 2005. Nucl Acids Res 2005; 33 (Suppl_1): D201–D205.

    PubMed  CAS  Google Scholar 

  31. Bairoch A, Boeckmann B . The SWISS-PROT protein sequence data bank. Nucleic Acids Res 1991; 19 (Suppl): 2247–2249.

    Article  CAS  Google Scholar 

  32. Kanehisa M . The KEGG database. Novartis Found Symp 2002; 247: 91–101.

    Article  CAS  Google Scholar 

  33. Zanzoni A, Montecchi-Palazzi L, Quondam M, Ausiello G, Helmer-Citterich M, Cesareni G . MINT: a Molecular INTeraction database. FEBS Lett 2002; 513: 135–140.

    Article  CAS  Google Scholar 

  34. Bader GD, Betel D, Hogue CW . BIND: the Biomolecular Interaction Network Database. Nucleic Acids Res 2003; 31: 248–250.

    Article  CAS  Google Scholar 

  35. Hermjakob H, Montecchi-Palazzi L, Lewington C, Mudali S, Kerrien S, Orchard S et al. IntAct: an open source molecular interaction database. Nucleic Acids Res 2004; 32 (Database issue): D452–D455.

    Article  CAS  Google Scholar 

  36. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D et al. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res 2003; 13: 2498–2504.

    Article  CAS  Google Scholar 

  37. Pavlidis P, Noble WS . Matrix2png: a utility for visualizing matrix data. Bioinformatics 2003; 19: 295–296.

    Article  CAS  Google Scholar 

  38. MacIntyre DJ, Blackwood DH, Porteous DJ, Pickard BS, Muir WJ . Chromosomal abnormalities and mental illness. Mol Psychiatry 2003; 8: 275–287.

    Article  CAS  Google Scholar 

  39. Demirhan O, Tastemir D . Chromosome aberrations in a schizophrenia population. Schizophr Res 2003; 65: 1–7.

    Article  Google Scholar 

  40. Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H et al. A human protein–protein interaction network: a resource for annotating the proteome. Cell 2005; 122: 957–968.

    Article  CAS  Google Scholar 

  41. Giot L, Bader JS, Brouwer C, Chaudhuri A, Kuang B, Li Y et al. A protein interaction map of Drosophila melanogaster. Science 2003; 302: 1727–1736.

    Article  CAS  Google Scholar 

  42. Brandon NJ, Schurov I, Camargo LM, Handford EJ, Duran-Jimeniz B, Hunt P et al. Subcellular targeting of DISC1 is dependent on a domain independent from the Nudel binding site. Mol Cell Neurosci 2005; 28: 613–624.

    Article  CAS  Google Scholar 

  43. James R, Adams RR, Christie S, Buchanan SR, Porteous DJ, Millar JK . Disrupted in schizophrenia 1 (DISC1) is a multicompartmentalized protein that predominantly localizes to mitochondria. Mol Cell Neurosci 2004; 26: 112–122.

    Article  CAS  Google Scholar 

  44. Toyo-oka K, Shionoya A, Gambello MJ, Cardoso C, Leventer R, Ward HL et al. 14-3-3epsilon is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller–Dieker syndrome. Nat Genet 2003; 34: 274–285.

    Article  CAS  Google Scholar 

  45. Reiner O, Cahana A, Escamez T, Martinez S . LIS1-no more no less. Mol Psychiatry 2002; 7: 12–16.

    Article  CAS  Google Scholar 

  46. Bateman J, Van Vactor D . The Trio family of guanine-nucleotide-exchange factors: regulators of axon guidance. J Cell Sci 2001; 114: 1973–1980.

    PubMed  CAS  Google Scholar 

  47. Fu CA, Shen M, Huang BCB, Lasaga J, Payan DG, Luo Y . TNIK, a novel member of the germinal center kinase family that activates the c-Jun N-terminal kinase pathway and regulates the cytoskeleton. J Biol Chem 1999; 274: 30729–30737.

    Article  CAS  Google Scholar 

  48. Wang X, Ching YP, Lam WH, Qi Z, Zhang M, Wang JH . Identification of a common protein association region in the neuronal Cdk5 activator. J Biol Chem 2000; 275: 31763–31769.

    Article  CAS  Google Scholar 

  49. Millar JK, Christie S, Porteous DJ . Yeast two-hybrid screens implicate DISC1 in brain development and function. Biochem Biophys Res Commun 2003; 311: 1019–1025.

    Article  CAS  Google Scholar 

  50. Zhang HT, Crissman AM, Dorairaj NR, Chandler LJ, O'Donnell JM . Inhibition of cyclic AMP phosphodiesterase (PDE4) reverses memory deficits associated with NMDA receptor antagonism. Neuropsychopharmacology 2000; 23: 198–204.

    Article  CAS  Google Scholar 

  51. Bresolin N, Castelli E, Comi GP, Felisari G, Bardoni A, Perani D et al. Cognitive impairment in Duchenne muscular dystrophy. Neuromuscul Disord 1994; 4: 359–369.

    Article  CAS  Google Scholar 

  52. Lehner B, Fraser AG . A first-draft human protein-interaction map. Genome Biol 2004; 5: R63.

    Article  Google Scholar 

  53. Spirin V, Mirny LA . Protein complexes and functional modules in molecular networks. Proc Natl Acad Sci USA 2003; 100: 12123–12128.

    Article  CAS  Google Scholar 

  54. von Mering C, Zdobnov EM, Tsoka S, Ciccarelli FD, Pereira-Leal JB, Ouzounis CA et al. Genome evolution reveals biochemical networks and functional modules. Proc Natl Acad Sci USA 2003; 100: 15428–15433.

    Article  CAS  Google Scholar 

  55. Ravasz E, Somera AL, Mongru DA, Oltvai ZN, Barabasi AL . Hierarchical organization of modularity in metabolic networks. Science 2002; 297: 1551–1555.

    Article  CAS  Google Scholar 

  56. Barabasi AL, Oltvai ZN . Network biology: understanding the cell's functional organization. Nat Rev Genet 2004; 5: 101–113.

    Article  CAS  Google Scholar 

  57. Whitford KL, Dijkhuizen P, Polleux F, Ghosh A . Molecular control of cortical dendrite development. Annu Rev Neurosci 2002; 25: 127–149.

    Article  CAS  Google Scholar 

  58. Li Z, Sheng M . Some assembly required: the development of neuronal synapses. Nat Rev Mol Cell Biol 2003; 4: 833–841.

    Article  CAS  Google Scholar 

  59. Lamprecht R, LeDoux J . Structural plasticity and memory. Nat Rev Neurosci 2004; 5: 45–54.

    Article  CAS  Google Scholar 

  60. Kennedy MB, Beale HC, Carlisle HJ, Washburn LR . Integration of biochemical signalling in spines. Nat Rev Neurosci 2005; 6: 423–434.

    Article  CAS  Google Scholar 

  61. Ziv NE, Garner CC . Cellular and molecular mechanisms of presynaptic assembly. Nat Rev Neurosci 2004; 5: 385–399.

    Article  CAS  Google Scholar 

  62. Collingridge GL, Isaac JT, Wang YT . Receptor trafficking and synaptic plasticity. Nat Rev Neurosci 2004; 5: 952–962.

    Article  CAS  Google Scholar 

  63. Klann E, Dever TE . Biochemical mechanisms for translational regulation in synaptic plasticity. Nat Rev Neurosci 2004; 5: 931–942.

    Article  CAS  Google Scholar 

  64. Sandi C . Stress, cognitive impairment and cell adhesion molecules. Nat Rev Neurosci 2004; 5: 917–930.

    Article  CAS  Google Scholar 

  65. Cbelos B, Gimenez C, Zafra F . The glycine transporter GLYT1 interacts with Sec3, a component of the exocyst complex. Neuropharmacology 2005; 20: 935–944.

    Article  CAS  Google Scholar 

  66. Sieburth D, Ch'ng Q, Dybbs M, Tavazoie M, Kennedy S, Wang D et al. Systematic analysis of genes required for synapse structure and function. Nature 2005; 436: 510–517.

    Article  CAS  Google Scholar 

  67. Sawa A, Snyder SH . Genetics. Two genes link two distinct psychoses. Science 2005; 310: 1128–1129.

    Article  CAS  Google Scholar 

  68. Thomson PA, Harris SE, Starr JM, Whalley LJ, Porteous DJ, Deary IJ . Association between genotype at an exonic SNP in DISC1 and normal cognitive aging. Neuroscience Lett 2005; 389: 41–45.

    Article  CAS  Google Scholar 

  69. Burdick KE, Hodgkinson CA, Szeszko PR, Lencz T, Ekholm JM, Kane JM et al. DISC1 and neurocognitive function in schizophrenia. Neuroreport 2005; 16: 1399–1402.

    Article  Google Scholar 

  70. Kamiya A, Kubo K, Tomoda T, Takaki M, Youn R, Ozeki Y et al. A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol 2005; 7: 1067–1078.

    Article  CAS  Google Scholar 

  71. Gandhi TK, Zhong J, Mathivanan S, Karthick L, Chandrika KN, Mohan SS et al. Analysis of the human protein interactome and comparison with yeast, worm and fly interaction datasets. Nat Genet 2006; 38: 285–293.

    Article  CAS  Google Scholar 

  72. Leung CL, Sun D, Zheng M, Knowles DR, Liem RK . Microtubule actin cross-linking factor (MACF): a hybrid of dystonin and dystrophin that can interact with the actin and microtubule cytoskeletons. J Cell Biol 1999; 147: 1275–1286.

    Article  CAS  Google Scholar 

  73. Yang Y, Bauer C, Strasser G, Wollman R, Julien JP, Fuchs E . Integrators of the cytoskeleton that stabilize microtubules. Cell 1999; 98: 229–238.

    Article  CAS  Google Scholar 

  74. Eastwood SL, McDonald B, Burnet PW, Beckwith JP, Kerwin RW, Harrison PJ . Decreased expression of mRNAs encoding non-NMDA glutamate receptors GluR1 and GluR2 in medial temporal lobe neurons in schizophrenia. Brain Res Mol Brain Res 1995; 29: 211–223.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Dr Miles Houslay and Dr Cem Elbi for input and discussions, Gianni Ceasareni and Luisa Montecchi-Palazzi for kindly providing us with releases of the MINT database, and Sue Ellis for kindly providing the figures for this work.

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Author notes

  1. N J Brandon

    Present address: Schizophrenia and Bipolar Research, Wyeth Discovery Neuroscience, CN8000, Princeton, NJ, 08543, USA

Authors and Affiliations

  1. Merck Research Labs, Merck & Co., Boston, MA, USA

    L M Camargo

  2. Department of Biochemistry, University of Cambridge, Cambridge, UK

    L M Camargo & K Mizuguchi

  3. HYBRIGENICS S.A., Paris, France

    V Collura & J-C Rain

  4. Centre for Mathematical Sciences, University of Cambridge, Cambridge, UK

    K Mizuguchi

  5. Department of Proteomics Services Group, European Bioinformatics Institute, EBI-Hinxton, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK

    H Hermjakob & S Kerrien

  6. Department of Molecular and Cellular Neurosciences, Merck Sharp and Dohme, The Neuroscience Research Centre, Harlow, Essex, UK

    L M Camargo, T P Bonnert, P J Whiting & N J Brandon

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Camargo, L., Collura, V., Rain, JC. et al. Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Mol Psychiatry 12, 74–86 (2007). https://doi.org/10.1038/sj.mp.4001880

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