Neurotherapeutics

, Volume 14, Issue 3, pp 623–629 | Cite as

Role of DISC1 in Neuronal Trafficking and its Implication in Neuropsychiatric Manifestation and Neurotherapeutics

  • Toshifumi Tomoda
  • Takatoshi Hikida
  • Takeshi Sakurai
Review

Abstract

Disrupted-in-schizophrenia 1 (DISC1) was initially identified as a gene disrupted by a translocation mutation co-segregating with a variety of psychotic and mood disorders in a Scottish pedigree. In agreement with this original finding, mouse models that perturb Disc1 display deficits of behaviors in specific dimensions, such as cognition and emotion, but not a motor dimension. Although DISC1 is not a risk gene for sporadic cases of specific psychiatric disorders defined by categorical diagnostic criteria (e.g., schizophrenia and major depressive disorder), DISC1 is now regarded as an important molecular lead to decipher molecular pathology for specific dimensions relevant to major mental illnesses. Emerging evidence points to the role of DISC1 in the regulation of intracellular trafficking of a wide range of neuronal cargoes. We will review recent progress in this aspect of DISC1 biology and discuss how we could utilize this body of knowledge to better understand the pathophysiology of mental illnesses.

Keywords

DISC1 Trafficking Interactome Cargo Schizophrenia 

Notes

Acknowledgements

We thank Dr. Akira Sawa (Johns Hopkins University) for advice. This work was supported by grants from DOD/CDMRP (W81XWH-11-1-0269) and CTF-DDI (TT), Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (15H04275, 16H06568 and 16 K14579 to TH; 15H01285 and 16 K01948 to TS), Takeda Science Foundation (TH), the Naito Foundation (TH), and the Kato Memorial Trust for Nambyo Research (TH). This work was performed, in part, under the International Cooperative Research Program of Institute for Protein Research, Osaka University, ICRa-17-13. The authors declare no conflict of interest.

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References

  1. 1.
    Brandon NJ, Sawa A. Linking neurodevelopmental and synaptic theories of mental illness through DISC1. Nat Rev Neurosci 2011;12:707-722.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Tomoda T, Sumitomo A, Jaaro-Peled H, Sawa A. Utility and validity of DISC1 mouse models in biological psychiatry. Neuroscience 2016;321:99-107.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Farrell MS, Werge T, Sklar P, et al. Evaluating historical candidate genes for schizophrenia. Mol Psychiatry 2015;20:555-562.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Mathieson I, Munafo MR, Flint J. Meta-analysis indicates that common variants at the DISC1 locus are not associated with schizophrenia. Mol Psychiatry 2012;17:634-641.CrossRefPubMedGoogle Scholar
  5. 5.
    Niwa M, Cash-Padgett T, Kubo KI, et al. DISC1 a key molecular lead in psychiatry and neurodevelopment: No-More Disrupted-in-Schizophrenia 1. Mol Psychiatry 2016;21:1488-1489.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Narayan S, Nakajima K, Sawa A. DISC1: a key lead in studying cortical development and associated brain disorders. Neuroscientist 2013;19:451-464.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Hayashi-Takagi A, Takaki M, Graziane N, et al. Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1. Nat Neurosci 2010;13:327-332.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Wang Q, Charych EI, Pulito VL, et al. The psychiatric disease risk factors DISC1 and TNIK interact to regulate synapse composition and function. Mol Psychiatry 2011;16:1006-1023.CrossRefPubMedGoogle Scholar
  9. 9.
    Hayashi-Takagi A, Araki Y, Nakamura M, et al. PAKs inhibitors ameliorate schizophrenia-associated dendritic spine deterioration in vitro and in vivo during late adolescence. Proc Natl Acad Sci U S A 2014;111:6461-6466.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Wei J, Graziane NM, Wang H, et al. Regulation of N-methyl-D-aspartate receptors by disrupted-in-schizophrenia-1. Biol Psychiatry 2014;75:414-424.CrossRefPubMedGoogle Scholar
  11. 11.
    Wen Z, Nguyen HN, Guo Z, et al. Synaptic dysregulation in a human iPS cell model of mental disorders. Nature 2014;515:414-418.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Seshadri S, Faust T, Ishizuka K, et al. Interneuronal DISC1 regulates NRG1-ErbB4 signalling and excitatory-inhibitory synapse formation in the mature cortex. Nat Commun 2015;6:10118.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Tsuboi D, Kuroda K, Tanaka M, et al. Disrupted-in-schizophrenia 1 regulates transport of ITPR1 mRNA for synaptic plasticity. Nat Neurosci 2015;18:698-707.CrossRefPubMedGoogle Scholar
  14. 14.
    Wei J, Graziane NM, Gu Z, Yan Z. DISC1 Protein regulates gamma-aminobutyric acid, type A (GABAA) receptor trafficking and inhibitory synaptic transmission in cortical neurons. J Biol Chem 2015;290:27680-27687.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Sawamura N, Sawa A. Disrupted-in-schizophrenia-1 (DISC1): a key susceptibility factor for major mental illnesses. Ann N Y Acad Sci 2006;1086:126-133.CrossRefPubMedGoogle Scholar
  16. 16.
    Ozeki Y, Tomoda T, Kleiderlein J, et al. Disrupted-in-Schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth. Proc Natl Acad Sci U S A 2003;100:289-294.CrossRefPubMedGoogle Scholar
  17. 17.
    Kamiya A, Kubo K, Tomoda T, et al. A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol 2005;7:1167-1178.CrossRefPubMedGoogle Scholar
  18. 18.
    Su P, Li S, Chen S, et al. A dopamine D2 receptor-DISC1 protein complex may contribute to antipsychotic-like effects. Neuron 2014;84:1302-1316.CrossRefPubMedGoogle Scholar
  19. 19.
    Camargo LM, 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 2007;12:74-86.CrossRefPubMedGoogle Scholar
  20. 20.
    Ogawa F, Malavasi EL, Crummie DK, et al. DISC1 complexes with TRAK1 and Miro1 to modulate anterograde axonal mitochondrial trafficking. Hum Mol Genet 2014;23:906-919.CrossRefPubMedGoogle Scholar
  21. 21.
    Norkett R, Modi S, Birsa N, et al. DISC1-dependent regulation of mitochondrial dynamics controls the morphogenesis of complex neuronal dendrites. J Biol Chem 2016;291:613-629.CrossRefPubMedGoogle Scholar
  22. 22.
    Flores R, 3rd, Hirota Y, Armstrong B, Sawa A, Tomoda T. DISC1 regulates synaptic vesicle transport via a lithium-sensitive pathway. Neurosci Res 2011;71:71-77.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Miyoshi K, Honda A, Baba K, et al. Disrupted-In-Schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth. Mol Psychiatry 2003;8:685-694.CrossRefPubMedGoogle Scholar
  24. 24.
    Taya S, Shinoda T, Tsuboi D, et al. DISC1 regulates the transport of the NUDEL/LIS1/14-3-3epsilon complex through kinesin-1. J Neurosci 2007;27:15-26.CrossRefPubMedGoogle Scholar
  25. 25.
    Saito A, Taniguchi Y, Rannals MD, et al. Early postnatal GABAA receptor modulation reverses deficits in neuronal maturation in a conditional neurodevelopmental mouse model of DISC1. Mol Psychiatry 2016;21:1449-1459.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Twelvetrees AE, Yuen EY, Arancibia-Carcamo IL, et al. Delivery of GABAARs to synapses is mediated by HAP1-KIF5 and disrupted by mutant huntingtin. Neuron 2010;65:53-65.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Nakajima K, Yin X, Takei Y, Seog DH, Homma N, Hirokawa N. Molecular motor KIF5A is essential for GABA(A) receptor transport, and KIF5A deletion causes epilepsy. Neuron 2012;76:945-961.CrossRefPubMedGoogle Scholar
  28. 28.
    Shahani N, Seshadri S, Jaaro-Peled H, et al. DISC1 regulates trafficking and processing of APP and Abeta generation. Mol Psychiatry 2015;20:874-879.CrossRefPubMedGoogle Scholar
  29. 29.
    Tanaka M, Ishizuka K, Nekooki-Machida Y, et al. Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington's disease. J Clin Invest 2017;127:1438-1450.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Murphy LC, Millar JK. Regulation of mitochondrial dynamics by DISC1, a putative risk factor for major mental illness. Schizophr Res 2017.Google Scholar
  31. 31.
    Atkin TA, MacAskill AF, Brandon NJ, Kittler JT. Disrupted in Schizophrenia-1 regulates intracellular trafficking of mitochondria in neurons. Mol Psychiatry 2011;16:122-124.CrossRefPubMedGoogle Scholar
  32. 32.
    Li Z, Okamoto K, Hayashi Y, Sheng M. The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 2004;119:873-887.CrossRefPubMedGoogle Scholar
  33. 33.
    Wang X, Schwarz TL. The mechanism of Ca2+-dependent regulation of kinesin-mediated mitochondrial motility. Cell 2009;136:163-174.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Macaskill AF, Rinholm JE, Twelvetrees AE, et al. Miro1 is a calcium sensor for glutamate receptor-dependent localization of mitochondria at synapses. Neuron 2009;61:541-555.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Brickley K, Stephenson FA. Trafficking kinesin protein (TRAK)-mediated transport of mitochondria in axons of hippocampal neurons. J Biol Chem 2011;286:18079-18092.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Shen S, Lang B, Nakamoto C, et al. Schizophrenia-related neural and behavioral phenotypes in transgenic mice expressing truncated Disc1. J Neurosci 2008;28:10893-10904.CrossRefPubMedGoogle Scholar
  37. 37.
    Kvajo M, McKellar H, Drew LJ, et al. Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice. Proc Natl Acad Sci U S A 2011;108:E1349-E1358.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Lepagnol-Bestel AM, Kvajo M, Karayiorgou M, Simonneau M, Gogos JA. A Disc1 mutation differentially affects neurites and spines in hippocampal and cortical neurons. Mol Cell Neurosci 2013;54:84-92.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Greenhill SD, Juczewski K, de Haan AM, Seaton G, Fox K, Hardingham NR. Adult cortical plasticity depends on an early postnatal critical period. Science 2015;349:424-427.CrossRefPubMedGoogle Scholar
  40. 40.
    Kulkarni VA, Firestein BL. The dendritic tree and brain disorders. Mol Cell Neurosci 2012;50:10-20.CrossRefPubMedGoogle Scholar
  41. 41.
    Park C, Lee SA, Hong JH, et al. Disrupted-in-schizophrenia 1 (DISC1) and Syntaphilin collaborate to modulate axonal mitochondrial anchoring. Mol Brain 2016;9:69.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Rizzuto R, De Stefani D, Raffaello A, Mammucari C. Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol 2012;13:566-578.CrossRefPubMedGoogle Scholar
  43. 43.
    Sakurai T, Ramoz N, Barreto M, et al. Slc25a12 disruption alters myelination and neurofilaments: a model for a hypomyelination syndrome and childhood neurodevelopmental disorders. Biol Psychiatry 2010;67:887-894.CrossRefPubMedGoogle Scholar
  44. 44.
    Park SJ, Jeong J, Park YU, et al. Disrupted-in-schizophrenia-1 (DISC1) regulates endoplasmic reticulum calcium dynamics. Sci Rep 2015;5:8694.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    van der Kant R, Goldstein LS. Cellular functions of the amyloid precursor protein from development to dementia. Dev Cell 2015;32:502-515.CrossRefPubMedGoogle Scholar
  46. 46.
    Smith KR, Kittler JT. The cell biology of synaptic inhibition in health and disease. Curr Opin Neurobiol 2010;20:550-556.CrossRefPubMedGoogle Scholar
  47. 47.
    Ishizuka K, Kamiya A, Oh EC, et al. DISC1-dependent switch from progenitor proliferation to migration in the developing cortex. Nature 2011;473:92-96.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Soda T, Frank C, Ishizuka K, et al. DISC1-ATF4 transcriptional repression complex: dual regulation of the cAMP-PDE4 cascade by DISC1. Mol Psychiatry 2013;18:898-908.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Trossbach SV, Bader V, Hecher L, et al. Misassembly of full-length Disrupted-in-Schizophrenia 1 protein is linked to altered dopamine homeostasis and behavioral deficits. Mol Psychiatry 2016;21:1561-1572.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Leliveld SR, Bader V, Hendriks P, et al. Insolubility of disrupted-in-schizophrenia 1 disrupts oligomer-dependent interactions with nuclear distribution element 1 and is associated with sporadic mental disease. J Neurosci 2008;28:3839-3845.CrossRefPubMedGoogle Scholar
  51. 51.
    Narayanan S, Arthanari H, Wolfe MS, Wagner G. Molecular characterization of disrupted in schizophrenia-1 risk variant S704C reveals the formation of altered oligomeric assembly. J Biol Chem 2011;286:44266-44276.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Atkin TA, Brandon NJ, Kittler JT. Disrupted in Schizophrenia 1 forms pathological aggresomes that disrupt its function in intracellular transport. Hum Mol Genet 2012;21:2017-2028.CrossRefPubMedGoogle Scholar
  53. 53.
    Boxall R, Porteous DJ, Thomson PA. DISC1 and Huntington's disease—overlapping pathways of vulnerability to neurological disorder? PLOS ONE 2011;6:e16263.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Nelson SB, Valakh V. Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders. Neuron 2015;87:684-698.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    World Health Organization. Shanghai declaration on promoting health in the 2030 Agenda for Sustainable Development. Health Promot Int 2017;32:7-8.CrossRefPubMedGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2017

Authors and Affiliations

  1. 1.Centre for Addiction and Mental HealthUniversity of TorontoTorontoCanada
  2. 2.Laboratory for Advanced Brain Functions, Institute for Protein ResearchOsaka UniversityOsakaJapan
  3. 3.Medical Innovation CenterKyoto University Graduate School of MedicineKyotoJapan

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