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Protein misassembly and aggregation as potential convergence points for non-genetic causes of chronic mental illness

Molecular Psychiatry volume 24, pages 936–951 (2019)Cite this article

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Abstract

Chronic mental illnesses (CMI), such as schizophrenia or recurrent affective disorders, are complex conditions with both genetic and non-genetic elements. In many other chronic brain conditions, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and frontotemporal dementia, sporadic instances of the disease are more common than gene-driven familial cases. Yet, the pathology of these conditions can be characterized by the presence of aberrant protein homeostasis, proteostasis, resulting in misfolded or aggregated proteins in the brains of patients that predominantly do not derive from genetic mutations. While visible deposits of aggregated protein have not yet been detected in CMI patients, we propose the existence of more subtle protein misassembly in these conditions, which form a continuum with the psychiatric phenotypes found in the early stages of many neurodegenerative conditions. Such proteinopathies need not rely on genetic variation. In a similar manner to the established aberrant neurotransmitter homeostasis in CMI, aberrant homeostasis of proteins is a functional statement that can only partially be explained by, but is certainly complementary to, genetic approaches. Here, we review evidence for aberrant proteostasis signatures from post mortem human cases, in vivo animal work, and in vitro analysis of candidate proteins misassembled in CMI. The five best-characterized proteins in this respect are currently DISC1, dysbindin-1, CRMP1, TRIOBP-1, and NPAS3. Misassembly of these proteins with inherently unstructured domains is triggered by extracellular stressors and thus provides a converging point for non-genetic causes of CMI.

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References

  1. Cardno AG, Owen MJ. Genetic relationships between schizophrenia, bipolar disorder, and schizoaffective disorder. Schizophr Bull. 2014;40:504–15.

    PubMed  PubMed Central  Google Scholar 

  2. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.

    PubMed Central  Google Scholar 

  3. Bustamante ML, Herrera L, Gaspar PA, Nieto R, Maturana A, Villar MJ, et al. Shifting the focus toward rare variants in schizophrenia to close the gap from genotype to phenotype. Am J Med Genet B Neuropscyhiatr Genet. 2017;174:663–70.

    Google Scholar 

  4. Pardinas AF, Holmans P, Pocklington AJ, Escott-Price V, Ripke S, Carrera N, et al. Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nat Genet. 2018;50:381–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Murray RM, Lewis SW. Is schizophrenia a neurodevelopmental disorder? Br J Med. 1987;295:681–2.

    CAS  Google Scholar 

  6. Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987;44:660–9.

    CAS  PubMed  Google Scholar 

  7. Rapoport JL, Giedd JN, Gogtay N. Neurodevelopmental model of schizophrenia: update 2012. Mol Psychiatry. 2012;17:1228–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Fromer M, Roussos P, Sieberts SK, Johnson JS, Kavanagh DH, Perumal TM, et al. Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci. 2016;19:1442–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Stern Y. Cognitive reserve and Alzheimer disease. Alzheimer Dis Assoc Disord. 2006;20(3 Suppl 2):S69–74.

    PubMed  Google Scholar 

  10. Fromer M, Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S, Gormley P, et al. De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014;506:179–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Taylor JP, Hardy J, Fischbeck KH. Toxic proteins in neurodegenerative disease. Science. 2002;296:1991–5.

    CAS  PubMed  Google Scholar 

  12. Alzheimer A. Über eine eigenartige Erkrankung der Hirnrinde. Cent Nerv Psychiatr. 1907;30:177–9.

    Google Scholar 

  13. Alzheimer A. Über eigenartige Krankheitsfälle des späteren Alters. Z Ges Neurol Psychiatr. 1911;4:356–85.

    Google Scholar 

  14. Hippius H, Neundorfer G. The discovery of Alzheimer’s disease. Dialogues Clin Neurosci. 2003;5:101–8.

    PubMed  PubMed Central  Google Scholar 

  15. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24:197–211.

    PubMed  Google Scholar 

  16. Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropath. 1991;82:239–59.

    CAS  PubMed  Google Scholar 

  17. Vilchez D, Simic MS, Dillin A. Proteostasis and aging of stem cells. Trends Cell Biol. 2014;24:161–70.

    CAS  PubMed  Google Scholar 

  18. Polajnar M, Žerovnik E. Impaired autophagy: a link between neurodegenerative and neuropsychiatric diseases. J Cell Mol Med. 2014;18:1705–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Guo JL, Lee VMY. Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat Med. 2014;20:130–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Prusiner SB. Shattuck Lecture -- neurodegenerative diseases and prions. N Engl J Med. 2001;344:1516–26.

    CAS  PubMed  Google Scholar 

  21. Bertram L, Lill CM, Tanzi RE. The genetics of Alzheimer disease: back to the future. Neuron. 2010;68:270–81.

    CAS  PubMed  Google Scholar 

  22. Uryu K, Chen X-H, Martinez D, Browne KD, Johnson VE, Graham DI, et al. Multiple proteins implicated in neurodegenerative diseases accumulate in axons after brain trauma in humans. Exp Neurol. 2007;208:185–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Johnson VE, Stewart W, Smith DH. Widespread tau and amyloid-beta pathology many years after a single traumatic brain injury in humans. Brain Pathol. 2012;22:142–9.

    CAS  PubMed  Google Scholar 

  24. Crane PK, Gibbons LE, Dams-O’Connor K, Trittschuh E, Leverenz JB, Keene CD, et al. Association of traumatic brain injury with late-life neurodegenerative conditions and neuropathologic findings. JAMA Neurol. 2016;73:1062–9.

    PubMed  PubMed Central  Google Scholar 

  25. Dyrks T, Dyrks E, Hartmann T, Masters C, Beyreuther K. Amyloidogenicity of βA4 and βA4-bearing amyloid protein precursor fragments by metal-catalyzed oxidation. J Biol Chem. 1992;267:18210–7.

    CAS  PubMed  Google Scholar 

  26. Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci. 2000;3:1301–6.

    CAS  PubMed  Google Scholar 

  27. Paxinou E, Chen Q, Weisse M, Giasson BI, Norris EH, Rueter SM, et al. Induction of α-synuclein aggregation by intracellular nitrative insult. J Neurosci. 2001;21:8053–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Cappai R, Leck S-L, Tew DJ, Williamson NA, Smith DP, Galatis D, et al. Dopamine promotes α-synuclein aggregation into SDS-resistant soluble oligomers via a distinct folding pathway. FASEB J. 2005;19:1377–9.

    CAS  PubMed  Google Scholar 

  29. Liu-Yesucevitz L, Bilgutay A, Zhang Y-J, Vanderwyde T, Citro A, Mehta T, et al. Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of culture cells and pathological brain tissue. PLoS ONE. 2010;5:e13250.

    PubMed  PubMed Central  Google Scholar 

  30. Uryu K, Laurer H, McIntosh T, Praticò D, Martinez D, Leight S, et al. Repetitive mild brain trauma accelerates Aβ deposition, lipid peroxication, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis. J Neurosci. 2002;22:446–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Yoshiyama Y, Uryu K, Higuchi M, Longhi L, Hoover R, Fujimoto S, et al. Enhanced neurofibrillary tangle formation, cerebral atrophy, and cognitive deficits induced by repeititve mild brain injury in a transgenic tauopathy mouse model. J Neurotrauma. 2005;22:1134–41.

    PubMed  Google Scholar 

  32. Knowles TPJ, Vendruscolo M, Dobson CM. The amyloid state and its association with protein misfolding diseases. Nat Rev Mol Cell Biol. 2014;15:384–96.

    CAS  PubMed  Google Scholar 

  33. Levine ZA, Larini L, LaPointe NE, Feinstein SC, Shea J-E. Regulation and aggregation of intrinsically disordered peptides. Proc Natl Acad Sci USA. 2015;112:2758–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Srivastava R, Faust T, Ramos A, Ishizuka K, Sawa A. Dynamic changes of the mitochondria in psychiatric illnesses: new mechanistic insights from human neuronal models. Biol Psychiatry. 2018;83:751–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM, Hatanpaa KJ, et al. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol. 2007;114:5–22.

    PubMed  PubMed Central  Google Scholar 

  36. Diekstra FP, Van Deerlin VM, van Swieten JC, Al-Chalabi A, Ludolph AC, Weishaupt JH, et al. C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: a genome-wide meta-analysis. Ann Neurol. 2014;76:120–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Woolley JD, Khan BK, Murthy NK, Miller BL, Rankin KP. The diagnostic challenge of psychiatric symptoms in neurodegenerative disease: rates of and risk factors for prior psychiatric diagnosis in patients with early neurodegenerative disease. J Clin Psychiatry. 2011;72:126–33.

    PubMed  PubMed Central  Google Scholar 

  38. Damier P, Hirsch EC, Agid Y, Graybiel AM. The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson’s disease. Brain. 1999;122(Pt 8):1437–48.

    PubMed  Google Scholar 

  39. Kirkwood SC, Su JL, Conneally PM, Foroud T. Progression of symptoms in the early and middle stages of Huntington disease. Arch Neurol. 2001;58:273–8.

    CAS  PubMed  Google Scholar 

  40. Huntington G. On chorea. Med Surg Rep. 1872;26:317–21.

    Google Scholar 

  41. Murray PS, Kumar S, Demichele-Sweet MA, Sweet RA. Psychosis in Alzheimer’s disease. Biol Psychiatry. 2014;75:542–52.

    PubMed  Google Scholar 

  42. Pressman PS, Miller BL. Diagnosis and management of behavioral variant frontotemporal dementia. Biol Psychiatry. 2014;75:574–81.

    PubMed  Google Scholar 

  43. Galimberti D, Dell’Osso B, Altamura AC, Scarpini E. Psychiatric symptoms in frontotemporal dementia: epidemiology, phenotypes, and differential diagnosis. Biol Psychiatry. 2015;78:684–92.

    PubMed  Google Scholar 

  44. Harciarek M, Malaspina D, Sun T, Goldberg E. Schizophrenia and frontotemporal dementia: shared causation? Int Rev Psychiatry. 2013;25:168–77.

    PubMed  Google Scholar 

  45. Weinberger DR. Schizophrenia and the frontal lobe. Trends Neurosci. 1988;11:367–70.

    CAS  PubMed  Google Scholar 

  46. Zanardini R, Ciani M, Benussi L, Ghidoni R. Molecular pathways bridging frontotemporal lobar degeneration and psychiatric disorders. Front Aging Neurosci. 2016;8:10.

    PubMed  PubMed Central  Google Scholar 

  47. Ventriglia M, Zanardini R, Bonomini C, Zanetti O, Volpe D, Pasqualetti P, et al. Serum brain-derived neurotrophic factor levels in different neurological diseases. Biomed Res Int. 2013;2013:901082.

    PubMed  PubMed Central  Google Scholar 

  48. Borroni B, Bianchi M, Premi E, Alberici A, Archetti S, Paghera B, et al. The brain-derived neurotrophic factor Val66Met polymorphism is associated with reduced hippocampus perfusion in frontotemporal lobar degeneration. J Alzheimer’s Dis. 2012;31:243–51.

    CAS  Google Scholar 

  49. Li M, Chan H, Xiao X. BDNF Val66Met polymorphism and bipolar disorder in European populations: a risk association in case-control, family-based and GWAS studies. Neurosci Biobehav Rev. 2016;68:218–33.

    CAS  PubMed  Google Scholar 

  50. Olszewska DA, Lonergan R, Fallon EM, Lynch T. Genetics of frontotemporal dementia. Curr Neurol Neurosci Rep. 2016;16:107.

    PubMed  Google Scholar 

  51. Schoder D, Hannequin D, Martinaud O, Opolczynski G, Guyant-Maréchal L, Le Ber I, et al. Morbid risk for schizophrenia in first-degree relatives of people with frontotemporal dementia. Br J Psychiatry. 2010;197:28–35.

    PubMed  Google Scholar 

  52. Carecchio M, Fenoglio C, De Riz M, Guidi I, Comi C, Cortini F, et al. Progranulin plasma levels as potential biomarker for the identification of GRN deletion carriers. A case with atypical onset as clinical amnestic mild cognitive impairment converted to Alzheimer’s disease. J Neurol Sci. 2009;287:291–3.

    CAS  PubMed  Google Scholar 

  53. Galimberti D, Dell’Osso B, Fenoglio C, Villa C, Cortini F, Serpente M, et al. Progranulin gene variability and plasma levels in bipolar disorder and schizophrenia. PLoS ONE. 2012;7:e32164.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med. 2013;368:107–16.

    CAS  PubMed  Google Scholar 

  55. Collste K, Plaven-Sigray P, Fatouros-Bergman H, Victorsson P, Schain M, Forsberg A, et al. Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and [(11)C]PBR28. Mol Psychiatry. 2017;22:850–6.

    CAS  PubMed  Google Scholar 

  56. Setiawan E, Attwells S, Wilson AA, Mizrahi R, Rusjan PM, Miler L, et al. Association of translocator protein total distribution volume with duration of untreated major depressive disorder: a cross-sectional study. Lancet Psychiatry. 2018;5:339–47.

    PubMed  Google Scholar 

  57. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314:130–3.

    CAS  PubMed  Google Scholar 

  58. Velakoulis D, Walterfang M, Mocellin R, Pantelis C, Dean B, McLean C. Abnormal hippocampal distribution of TDP-43 in patients with-late onset psychosis. Aus N Z J Psychiatry. 2009;43:739–45.

    Google Scholar 

  59. Mateen FJ, Josephs KA. TDP-43 is not present in brain tissue of patients with schizophrenia. Schizophr Res. 2009;108:297–8.

    PubMed  Google Scholar 

  60. Geser F, Robinson JL, Malunda JA, Xie SX, Clark CM, Kwong LK, et al. Pathological 43-kDa transactivation response DNA-binding protein in older adults with and without severe mental illness. Arch Neurol. 2010;67:1238–50.

    PubMed  PubMed Central  Google Scholar 

  61. Endo R, Takashima N, Nekooki-Machida Y, Komi Y, Hui KK-W, Takao M, et al. TDP-43 and DISC1 co-aggregation disrupts dendritic local translation and mental function in FTLD. Biol Psychiatry. 2018; https://doi.org/10.1016/j.biopsych.2018.03.008.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Tanaka M, Ishizuka K, Nekooki-Machida Y, Endo R, Takashima N, Sasaki H, et al. Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington’s disease. J Clin Invest. 2017;127:1438–50.

    PubMed  PubMed Central  Google Scholar 

  63. Bruton CJ, Crow TJ, Frith CD, Johnstone EC, Owens DGC, Roberts GW. Schizophrenia and the brain: a prospective clinico-neuropathological study. Psychol Med. 1990;20:285–304.

    CAS  PubMed  Google Scholar 

  64. Religa D, Laudon H, Styczynska M, Winblad B, Näslud J, Haroutunian V. Amyloid β pathology in Alzheimer’s disease and schizophrenia. Am J Psychiatry. 2003;160:867–72.

    PubMed  Google Scholar 

  65. Jellinger KA. Lewy body/α-synucleinopathy in schizophrenia and depression: a preliminary neuropathological study. Acta Neuropathol. 2009;117:423–7.

    CAS  PubMed  Google Scholar 

  66. Gibson J, Russ TC, Adams MJ, Clarke TK, Howard DM, Hall LS, et al. Assessing the presence of shared genetic architecture between Alzheimer’s disease and major depressive disorder using genome-wide association data. Transl Psychiatry. 2017;7:e1094.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Leliveld SR, Bader V, Hendriks P, Prikulis I, Sajnani G, Requena JR, 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;28:3839–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Ottis P, Bader V, Trossbach SV, Kretzschmar H, Michel M, Leliveld SR, et al. Convergence of two independent mental disease genes on the protein level: recruitment of dysbindin to cell-invasive Disrupted-in-Schizophrenia 1 aggresomes. Biol Psychiatry. 2011;70:604–10.

    CAS  PubMed  Google Scholar 

  69. Nucifora LG, Wu YC, Lee BJ, Sha L, Margolis RL, Ross CA, et al. A mutation in NPAS3 that segregates with schizophrenia in a small family leads to protein aggregation. Mol Neuropsychiatry. 2016;2:133–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Bader V, Tomppo L, Trossbach SV, Bradshaw NJ, Prikulis I, Leliveld SR, et al. Proteomic, genomic and translational approaches identify CRMP1 for a role in schizophrenia and its underlying traits. Hum Mol Genet. 2012;21:4406–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Bradshaw NJ, Bader V, Prikulis I, Lueking A, Müllner S, Korth C. Aggregation of the protein TRIOBP-1 and its potential relevance to schizophrenia. PLoS ONE. 2014;9:e111196.

    PubMed  PubMed Central  Google Scholar 

  72. Brandon NJ, Sawa A. Linking neurodevelopmental and synaptic theories of mental illness through DISC1. Nat Rev Neurosci. 2011;12:707–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Yerabham ASK, Weiergräber OH, Bradshaw NJ, Korth C. Revisiting Disrupted in Schizophrenia 1 as a scaffold protein. Biol Chem. 2013;394:1425–37.

    CAS  PubMed  Google Scholar 

  74. Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CAM, et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet. 2000;9:1415–25.

    CAS  PubMed  Google Scholar 

  75. Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK. The DISC locus in psychiatric illness. Mol Psychiatry. 2008;13:36–64.

    CAS  PubMed  Google Scholar 

  76. Thomson PA, Malavasi ELV, Grünewald E, Soares DC, Borkowska M, Millar JK. DISC1 genetics, biology and psychiatric illness. Front Biol. 2013;8:1–31.

    CAS  Google Scholar 

  77. Sullivan PF. Questions about DISC1 as a genetic risk factor for schizophrenia. Mol Psychiatry. 2013;18:1050–2.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Porteous DJ, Thomson PA, Millar JK, Evans KL, Hennah W, Soares DC, et al. DISC1 as a genetic risk factor for schizophrenia and related major mental illness: response to Sullivan. Mol Psychiatry. 2014;19:141–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Farrell MS, Werge T, Sklar P, Owen MJ, Ophoff RA, O’Donovan MC, et al. Evaluating historical candidate genes for schizophrenia. Mol Psychiatry. 2015;20:555–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Niwa M, Cash-Padgett T, Kubo KI, Saito A, Ishii K, Sumitomo A, et al. DISC1 a key molecular lead in psychiatry and neurodevelopment: No-More Disrupted-in-Schizophrenia 1. Mol Psychiatry. 2016;21:1488–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Ishizuka K, Kamiya A, Oh EC, Kanki H, Seshadri S, Robinson JF, et al. DISC1-dependent switch from progenitor proliferation to migration in the developing cortex. Nature. 2011;473:92–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Trossbach SV, Bader V, Hecher L, Pum ME, Masoud ST, Prikulis I, et al. Misassembly of full-length Disrupted-in-Schizophrenia 1 protein is linked to altered dopamine homeostasis and behavioral deficits. Mol Psychiatry. 2016;21:1561–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Atkin TA, Brandon NJ, Kittler JT. Disrupted in Schizophrenia 1 forms pathological aggresomes that disrupt its function in intracellular transport. Hum Mol Genet. 2012;21:2017–28.

    CAS  PubMed  Google Scholar 

  84. Wang A-L, Fazari B, Chao OY, Nikolaus S, Trossbach SV, Korth C, et al. Intra-nasal dopamine alleviates cognitive deficits in tgDISC1 rats which over-express the human DISC1 gene. Neurobiol Learn Memory. 2017; https://doi.org/10.1016/j.nlm.2017.10.015.

    CAS  PubMed  Google Scholar 

  85. Seeman P. Schizophrenia and dopamine receptors. Eur Neuropsychopharmacol. 2013;23:999–1009.

    CAS  PubMed  Google Scholar 

  86. Hamburg H, Trossbach SV, Bader V, Chwiesko C, Kipar A, Sauvage M, et al. Simultaneous effects on parvalbumin-positive interneuron and dopaminergic system development in a transgenic rat model for sporadic schizophrenia. Sci Rep. 2016;6:34946.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Zhu S, Abounit S, Korth C, Zurzolo C. Transfer of Disrupted-in-Schizophrenia 1 aggregates between neuronal-like cells occurs in tunnelling nanotubes and is promoted by dopamine. Open Biol. 2017;7:160328.

    PubMed  PubMed Central  Google Scholar 

  88. Bader V, Ottis P, Pum M, Huston JP, Korth C. Generation, purification, and characterization of cell-invasive DISC1 protein species. J Vis Exp. 2012;e4132.

  89. Zhou X, Geyer MA, Kelsoe JR. Does Disrupted-in-Schizophrenia (DISC1) generate fusion transcripts? Mol Psychiatry. 2008;13:361–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Zhou X, Chen Q, Schaukowitch K, Kelsoe JR, Geyer MA. Insoluble DISC1–Boymaw fusion proteins generated by DISC1 translocation. Mol Psychiatry. 2010;15:670–5.

    PubMed Central  Google Scholar 

  91. Eykelenboom JE, Briggs GJ, Bradshaw NJ, Soares DC, Ogawa F, Christie S, et al. A t(1;11) translocation linked to schizophrenia and affective disorders gives rise to aberrant chimeric DISC1 transcripts that encode structurally altered, deleterious mitochondrial proteins. Hum Mol Genet. 2012;21:3374–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Sachs NA, Sawa A, Holmes SE, Ross CA, DeLisi LE, Margolis RL. A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder. Mol Psychiatry. 2005;10:758–64.

    CAS  PubMed  Google Scholar 

  93. Wen Z, Nguyen HN, Guo Z, Lalli MA, Wang X, Su Y, et al. Synaptic dysregulation in a human iPS cell model of mental disorders. Nature. 2014;515:414–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Yerabham ASK, Mas PJ, Decker C, Soares DC, Weiergräber OH, Nagel-Steger L, et al. A structural organization for Disrupted in Schizophrenia 1, identified by high-throughput screening, reveals distinctly folded regions which are bisected by mental illness-related mutations. J Biol Chem. 2017;292:6468–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Shahani N, Seshadri S, Jaaro-Peled H, Ishizuka K, Hirota-Tsuyada Y, Wang Q, et al. DISC1 regulates trafficking and processing of APP and Aβ generation. Mol Psychiatry. 2015;20:874–9.

    CAS  PubMed  Google Scholar 

  96. Deng Q-S, Dong X-Y, Wu H, Wang W, Wang Z-T, Zhu J-W, et al. Disrupted-in-Schizophrenia-1 attenuates amyloid-β generation and cognitive deficits in APP/PS1 transgenic mice by reduction of β-site APP-cleaving enzyme 1 levels. Neuropharmacology. 2016;41:440–63.

    CAS  Google Scholar 

  97. Straub RE, Jiang Y, MacLean CJ, Ma Y, Webb BT, Myakishev MV, et al. Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. Am J Hum Genet. 2002;71:337–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Li W, Zhang Q, Oiso N, Novak EK, Gautam R, O’Brien EP, et al. Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Nat Genet. 2003;35:84–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Hoe H-S, Fu Z, Makarova A, Lee J-Y, Lu C, Feng L, et al. The effects of amyloid precursor protein on postsynaptic composition and activity. J Biol Chem. 2009;284:8495–506.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Ji Y, Yang F, Papaleo F, Wang H-X, Gao W-J, Weinberger DR, et al. Role of dysbindin in dopamine receptor trafficking and cortical GABA function. Proc Natl Acad Sci USA. 2009;106:19593–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Xu Y, Sun Y, Ye H, Zhu L, Liu J, Wu X, et al. Increased dysbindin-1B isoform expression in schizophrenia and its propensity in aggresome formation. Cell Discov. 2015;1:15032.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Zhu C-Y, Shen Y, Xu Q. Propagation of dysbindin-1B aggregates: exosome-mediated transmission of neurotoxic deposits. Neuroscience. 2015;291:301–16.

    CAS  PubMed  Google Scholar 

  103. Yang W, Zhu C, Shen Y, Xu Q. The pathogenic mechanism of dysbindin-1B toxic aggregation: BLOC-1 and intercellular vesicle trafficking. Neuroscience. 2016;333:78–91.

    CAS  PubMed  Google Scholar 

  104. Yamashita N, Goshima Y. Collapsin response mediator proteins regulate neuronal development and plasticity by switching their phosphorylation status. Mol Neurobiol. 2012;45:234–46.

    CAS  PubMed  Google Scholar 

  105. Nakamura F, Kumeta K, Hida T, Isono T, Nakayama Y, Kuramata-Matsuoka E, et al. Amino- and carboxyl-terminal domains of filamin-A interact with CRMP1 to mediate Sema3A signalling. Nat Commun. 2014;5:5325.

    CAS  PubMed  Google Scholar 

  106. Johnston-Wilson NL, Sims CD, Hofmann J-P, Anderson L, Shore AD, Torrey EF, et al. Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. Mol Psychiatry. 2000;5:142–9.

    CAS  PubMed  Google Scholar 

  107. Beasley CL, Pennington K, Behan A, Wait R, Dunn MJ, Cotter D. Proteomic analysis of the anterior cingulate cortex in the major psychiatric disorders: evidence for disease-associated changes. Proteomics. 2006;6:3414–25.

    CAS  PubMed  Google Scholar 

  108. Stroedicke M, Bounab Y, Strempel N, Klockmeier K, Yigit S, Friedrich RP, et al. Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity. Genome Res. 2015;25:701–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Seipel K, O’Brien SP, Iannotti E, Medley QG, Streuli M. Tara, a novel F-actin binding protein, associates with the Trio guanine nucleotide exchange factor and regulates actin cytoskeletal organization. J Cell Sci. 2001;114(Pt 2):389–99.

    CAS  PubMed  Google Scholar 

  110. Bradshaw NJ, Yerabham ASK, Marreiros R, Zhang T, Nagel-Steger L, Korth C. An unpredicted aggregation-critical region of the actin-polymerizing protein TRIOBP-1/Tara, determined by elucidation of its domain structure. J Biol Chem. 2017;292:9583–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Hong J-H, Kwak Y, Woo Y, Park C, Lee S-A, Lee H, et al. Regulation of the actin cytoskeleton by the Ndel1-Tara complex is critical for cell migration. Sci Rep. 2016;6:31827.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Zhu Y, Wang C, Lan J, Yu J, Jin C, Huang H. Phosphorylation of Tara by Plk1 is essential for faithful chromosome segregation in mitosis. Exp Cell Res. 2012;318:2344–52.

    CAS  PubMed  Google Scholar 

  113. Maycox PR, Kelly F, Taylor A, Bates S, Reid J, Logendra R, et al. Analysis of gene expression in two large schizophrenia cohorts identifies multiple changes associated with nerve terminal function. Mol Psychiatry. 2009;14:1083–94.

    CAS  PubMed  Google Scholar 

  114. Yu J, Lan J, Zhu Y, Li X, Lai X, Xue Y, et al. The E3 ubiquitin ligase HECTD3 regulates ubiquitination and degradation of Tara. Biochem Biophys Res Commun. 2008;367:805–12.

    CAS  PubMed  Google Scholar 

  115. Brunskill EW, Witte DP, Shreiner AB, Potter SS. Characterization of Npas3, a novel basic helix-loop-helix PAS gene expressed in the developing mouse nervous system. Mech Dev. 1999;88:237–41.

    CAS  PubMed  Google Scholar 

  116. Kamnasaran D, Muir WJ, Ferguson-Smith MA, Cox DW. Disruption of the neuronal PAS3 gene in a family affected with schizophrenia. J Med Genet. 2003;40:325–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Pickard BS, Malloy MP, Porteous DJ, Blackwood DHR, Muir WJ. Disruption of a brain transcription factor, NPAS3, is associated with schizophrenia and learning disability. Am J Med Genet B Neuropsychiatr Genet. 2005;136B:26–32.

    PubMed  Google Scholar 

  118. Yu L, Arbez N, Nucifora LG, Sell GL, DeLisi LE, Ross CA, et al. A mutation in NPAS3 segregates with mental illness in a small family. Mol Psychiatry. 2014;19:7–8.

    CAS  PubMed  Google Scholar 

  119. Brandon NJ, Schurov I, Camargo LM, Handford EJ, Duran-Jimeriz B, Hunt P, et al. Subcellular targetting of DISC1 is dependant on a domain independent from the Nudel binding site. Mol Cell Neurosci. 2005;28:613–24.

    CAS  PubMed  Google Scholar 

  120. Leliveld SR, Hendriks P, Michel M, Sajnani G, Bader V, Trossbach S, et al. Oligomer assembly of the C-terminal DISC1 domain (640-854) is controlled by self-association motifs and disease-associated polymorphism S704C. Biochemistry. 2009;48:7746–55.

    CAS  PubMed  Google Scholar 

  121. Ward JJ, Sodhi JS, McGuffin LJ, Buxton BF, Jones DT. Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. J Mol Biol. 2004;337:635–45.

    CAS  PubMed  Google Scholar 

  122. Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III--the final common pathway. Schizophr Bull. 2009;35:549–62.

    PubMed  PubMed Central  Google Scholar 

  123. Gonzalez de San Roman E, Bidmon HJ, Malisic M, Susnea I, Kuppers A, Hubbers R, et al. Molecular composition of the human primary visual cortex profiled by multimodal mass spectrometry imaging. Brain Struct Funct. 2018;223:2767–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Zhang S, Smailagic N, Hyde C, Noel-Storr AH, Takwoingi Y, McShane R, et al. (11)C-PIB-PET for the early diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev. 2014;CD010386.

  125. Badhwar A, Tam A, Dansereau C, Orban P, Hoffstaedter F, Bellec P. Resting-state network dysfunction in Alzheimer’s disease: a systematic review and meta-analysis. Alzheimers Dement. 2017;8:73–85.

    Google Scholar 

  126. Hoenig MC, Bischof GN, Seemiller J, Hammes J, Kukolja J, Onur OA, et al. Networks of tau distribution in Alzheimer’s disease. Brain. 2018;141:568–81.

    PubMed  Google Scholar 

  127. Mirza SS, Ikram MA, Bos D, Mihaescu R, Hofman A, Tiemeier H. Mild cognitive impairment and risk of depression and anxiety: a population-based study. Alzheimers Dement. 2017;13:130–9.

    PubMed  Google Scholar 

  128. Ismail Z, Elbayoumi H, Fischer CE, Hogan DB, Millikin CP, Schweizer T, et al. Prevalence of depression in patients with mild cognitive impairment: a systematic review and meta-analysis. JAMA Psychiatry. 2017;74:58–67.

    PubMed  Google Scholar 

  129. Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry. 2006;63:530–8.

    PubMed  PubMed Central  Google Scholar 

  130. Harrison PJ. The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology. 2004;174:151–62.

    CAS  PubMed  Google Scholar 

  131. Sweet RA, Hamilton RL, Butters MA, Mulsant BH, Pollock BG, Lewis DA, et al. Neuropathologic correlates of late-onset major depression. Neuropsychopharmacology. 2004;29:2242–50.

    PubMed  Google Scholar 

  132. Gabilondo A, Alonso-Moran E, Nuno-Solinis R, Orueta JF, Iruin A. Comorbidities with chronic physical conditions and gender profiles of illness in schizophrenia. Results from PREST, a new health dataset. J Psychosom Res. 2017;93:102–9.

    PubMed  Google Scholar 

  133. Nalls MA, Saad M, Noyce AJ, Keller MF, Schrag A, Bestwick JP, et al. Genetic comorbidities in Parkinson’s disease. Hum Mol Genet. 2014;23:831–41.

    CAS  PubMed  Google Scholar 

  134. Schuurman AG, van den Akker M, Ensinck KT, Metsemakers JF, Knottnerus JA, Leentjens AF, et al. Increased risk of Parkinson’s disease after depression: a retrospective cohort study. Neurology. 2002;58:1501–4.

    CAS  PubMed  Google Scholar 

  135. Byrne S, Heverin M, Elamin M, Bede P, Lynch C, Kenna K, et al. Aggregation of neurologic and neuropsychiatric disease in amyotrophic lateral sclerosis kindreds: a population-based case-control cohort study of familial and sporadic amyotrophic lateral sclerosis. Ann Neurol. 2013;74:699–708.

    PubMed  Google Scholar 

  136. McLaughlin RL, Schijven D, van Rheenen W, van Eijk KR, O’Brien M, Kahn RS, et al. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia. Nat Commun. 2017;8:14774.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. O’Brien M, Burke T, Heverin M, Vajda A, McLaughlin R, Gibbons J, et al. Clustering of neuropsychiatric disease in first-degree and second-degree relatives of patients with amyotrophic lateral sclerosis. JAMA Neurol. 2017;74:1425–30.

    PubMed  PubMed Central  Google Scholar 

  138. McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Daneshvar DH, et al. The spectrum of disease in chronic traumatic encephalopathy. Brain. 2013;136(Pt 1):43–64.

    PubMed  Google Scholar 

  139. Kazmierczak M, Kazmierczak P, Peng AW, Harris SL, Shah P, Puel J-L, et al. Pejvakin, a candidate stereociliary rootlet protein, regulates hair cell function in a cell-autonomous manner. J Neurosci. 2017;37:3447–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Jones DK, Johnson AC, Roti Roti EC, Liu F, Uelmen R, Ayers RA, et al. Localization and functional consequences of a direct interaction between TRIOBP-1 and hERG/KCNH2 proteins in the heart. J Cell Sci. 2018;131:jcs206730.

    PubMed  PubMed Central  Google Scholar 

  141. Ishida T, Kinoshita K. Prediction of disordered regions in proteins based on the meta approach. Bioinformatics. 2008;24:1344–8.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Jesús Requena for discussion concerning this manuscript. This work was funded by the Fritz Thyssen Stiftung (10.14.2.140 to N.J.B.), the EU Seventh Framework Program (MC-IN “IN-SENS” #60761 to C.K.), the Brain Behavior Research Foundation (NARSAD Independent Investigator Award #20350 to C.K.), and a grant from the Research Commission of the Medical Faculty of the HHU (#9772651).

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  1. Department of Biotechnology, University of Rijeka, Rijeka, Croatia

    Nicholas J. Bradshaw

  2. Department of Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    Carsten Korth

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Bradshaw, N.J., Korth, C. Protein misassembly and aggregation as potential convergence points for non-genetic causes of chronic mental illness. Mol Psychiatry 24, 936–951 (2019). https://doi.org/10.1038/s41380-018-0133-2

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