Aberrant glycosylation in schizophrenia: a review of 25 years of post-mortem brain studies

Abstract

Glycosylation, the enzymatic attachment of carbohydrates to proteins and lipids, regulates nearly all cellular processes and is critical in the development and function of the nervous system. Axon pathfinding, neurite outgrowth, synaptogenesis, neurotransmission, and many other neuronal processes are regulated by glycans. Over the past 25 years, studies analyzing post-mortem brain samples have found evidence of aberrant glycosylation in individuals with schizophrenia. Proteins involved in both excitatory and inhibitory neurotransmission display altered glycans in the disease state, including AMPA and kainate receptor subunits, glutamate transporters EAAT1 and EAAT2, and the GABAA receptor. Polysialylated NCAM (PSA-NCAM) and perineuronal nets, highly glycosylated molecules critical for axonal migration and synaptic stabilization, are both downregulated in multiple brain regions of individuals with schizophrenia. In addition, enzymes spanning several pathways of glycan synthesis show differential expression in brains of individuals with schizophrenia. These changes may be due to genetic predisposition, environmental perturbations, medication use, or a combination of these factors. However, the recent association of several enzymes of glycosylation with schizophrenia by genome-wide association studies underscores the importance of glycosylation in this disease. Understanding how glycosylation is dysregulated in the brain will further our understanding of how this pathway contributes to the development and pathophysiology of schizophrenia.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Glycoproteins and glycoenzymes altered in schizophrenia based on gene expression and post-mortem studies.

References

  1. 1.

    Reily C, Stewart TJ, Renfrow MB, Novak J. Glycosylation in health and disease. Nat Rev Nephrol. 2019;15:346–66.

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Ng BG, Freeze HH. Perspectives on glycosylation and its congenital disorders. Trends Genet. 2018;34:466–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Chang IJ, He M, Lam CT. Congenital disorders of glycosylation. Ann Transl Med. 2018;6:477.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Freeze HH, Eklund EA, Ng BG, Patterson MC. Neurological aspects of human glycosylation disorders. Annu Rev Neurosci. 2015;38:105–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Scott H, Panin VM. The role of protein N-glycosylation in neural transmission. Glycobiology. 2014;24:407–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Cai G, Salonikidis PS, Fei J, Schwarz W, Schülein R, Reutter W, et al. The role of N-glycosylation in the stability, trafficking and GABA-uptake of GABA-transporter 1. Terminal N-glycans facilitate efficient GABA-uptake activity of the GABA transporter. FEBS J. 2005;272:1625–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Kandel MB, Yamamoto S, Midorikawa R, Morise J, Wakazono Y, Oka S, et al. N-glycosylation of the AMPA-type glutamate receptor regulates cell surface expression and tetramer formation affecting channel function. J Neurochem. 2018;147:730–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Storey GP, Opitz-Araya X, Barria A. Molecular determinants controlling NMDA receptor synaptic incorporation. J Neurosci. 2011;31:6311–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Lichnerova K, Kaniakova M, Park SP, Skrenkova K, Wang Y-X, Petralia RS, et al. Two N-glycosylation Sites in the GluN1 subunit are essential for releasing N-methyl-d-aspartate (NMDA) receptors from the endoplasmic reticulum. J Biol Chem. 2015;290:18379–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Skrenkova K, Lee S, Lichnerova K, Kaniakova M, Hansikova H, Zapotocky M, et al. N-glycosylation regulates the trafficking and surface mobility of GluN3A-containing NMDA receptors. Front Mol Neurosci. 2018;11:118.

  11. 11.

    Min C, Zheng M, Zhang X, Guo S, Kwon K-J, Shin CY, et al. N-linked glycosylation on the N-terminus of the dopamine D2 and D3 receptors determines receptor association with specific microdomains in the plasma membrane. Biochim Biophys Acta. 2015;1853:41–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Iqbal S, Ghanimi Fard M, Everest-Dass A, Packer NH, Parker LM Understanding cellular glycan surfaces in the central nervous system. Biochem Soc Trans. 2018. https://doi.org/10.1042/BST20180330.

  13. 13.

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

    Google Scholar 

  14. 14.

    Mealer RG, Williams SE, Daly MJ, Scolnick EM, Cummings RD, Smoller JW. Glycobiology and schizophrenia: a biological hypothesis emerging from genomic research. Mol Psychiatry. https://doi.org/10.1038/s41380-020-0753-1 (2020).

  15. 15.

    Varki A. Biological roles of glycans. Glycobiology. 2017;27:3–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Henrissat B, Surolia A, Stanley P A Genomic View of Glycobiology. In: Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, et al., editors. Essent. Glycobiol, 3rd ed. Cold Spring Harbor NY: Cold Spring Harbor Laboratory Press; 2015.

  17. 17.

    Moremen KW, Tiemeyer M, Nairn AV. Vertebrate protein glycosylation: diversity, synthesis and function. Nat Rev Mol Cell Biol. 2012;13:448–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Schwarz F, Aebi M. Mechanisms and principles of N-linked protein glycosylation. Curr Opin Struct Biol. 2011;21:576–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Stanley P, Taniguchi N, Aebi M N-Glycans. In: Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, et al., editors. Essentials Glycobiol, 3rd ed. Cold Spring Harbor NY: Cold Spring Harbor Laboratory Press; 2015.

  20. 20.

    Joshi HJ, Narimatsu Y, Schjoldager KT, Tytgat HLP, Aebi M, Clausen H, et al. SnapShot: O-glycosylation pathways across kingdoms. Cell. 2018;172:632–632.e2.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Brockhausen I, Stanley P O-GalNAc Glycans. In: Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, et al., editors. Essentials Glycobiol, 3rd ed. Cold Spring Harbor NY: Cold Spring Harbor Laboratory Press; 2015.

  22. 22.

    Haltiwanger RS, Wells L, Freeze HH, Stanley P. Other Classes of Eukaryotic Glycans. In: Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, et al., editors. Essentials Glycobiol,. 3rd ed. Cold Spring Harbor NY: Cold Spring Harbor Laboratory Press; 2015.

  23. 23.

    Schnaar RL The Biology of Gangliosides. Adv. Carbohydr. Chem. Biochem, 76, Elsevier; 2019. p. 113–48.

  24. 24.

    Schnaar RL, Kinoshita T Glycosphingolipids. In: Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, et al., editors. Essentials Glycobiol, 3rd ed. Cold Spring Harbor NY: Cold Spring Harbor Laboratory Press; 2015.

  25. 25.

    Marcus J, Honigbaum S, Shroff S, Honke K, Rosenbluth J, Dupree JL. Sulfatide is essential for the maintenance of CNS myelin and axon structure. Glia. 2006;53:372–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Lindahl U, Couchman J, Kimata K, Esko JD. Proteoglycans and sulfated glycosaminoglycans. In: Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, et al., editors. Essentials Glycobiol, 3rd ed. Cold Spring Harbor NY: Cold Spring Harbor Laboratory Press; 2015.

  27. 27.

    Rowlands D, Sugahara K, Kwok J. Glycosaminoglycans and glycomimetics in the central nervous system. Molecules. 2015;20:3527–48.

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Hansen L, Lind-Thomsen A, Joshi HJ, Pedersen NB, Have CT, Kong Y, et al. A glycogene mutation map for discovery of diseases of glycosylation. Glycobiology. 2015;25:211–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Joshi HJ, Hansen L, Narimatsu Y, Freeze HH, Henrissat B, Bennett E, et al. Glycosyltransferase genes that cause monogenic congenital disorders of glycosylation are distinct from glycosyltransferase genes associated with complex diseases. Glycobiology. 2018;28:284–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, et al., editors. Essentials of Glycobiology. 3rd ed. Cold Spring Harbor NY: Cold Spring Harbor Laboratory Press; 2015.

  31. 31.

    Tucholski J, Simmons MS, Pinner AL, Haroutunian V, McCullumsmith RE, Meador-Woodruff JH. Abnormal N-linked glycosylation of cortical AMPA receptor subunits in schizophrenia. Schizophr Res. 2013;146:177–83.

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Tucholski J, Simmons MS, Pinner AL, McMillan LD, Haroutunian V, Meador-Woodruff JH. N-linked glycosylation of cortical N-methyl-D-aspartate and kainate receptor subunits in schizophrenia. Neuroreport. 2013;24:688–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Bauer D, Haroutunian V, Meador-Woodruff JH, McCullumsmith RE. Abnormal glycosylation of EAAT1 and EAAT2 in prefrontal cortex of elderly patients with schizophrenia. Schizophr Res. 2010;117:92–98.

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Mueller TM, Haroutunian V, Meador-Woodruff JH. N-glycosylation of GABAA receptor subunits is altered in schizophrenia. Neuropsychopharmacol. 2014;39:528–37.

    CAS  Google Scholar 

  35. 35.

    Barbeau D, Liang JJ, Robitalille Y, Quirion R, Srivastava LK. Decreased expression of the embryonic form of the neural cell adhesion molecule in schizophrenic brains. Proc Natl Acad Sci USA. 1995;92:2785–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Gilabert-Juan J, Varea E, Guirado R, Blasco-Ibáñez JM, Crespo C, Nácher J. Alterations in the expression of PSA-NCAM and synaptic proteins in the dorsolateral prefrontal cortex of psychiatric disorder patients. Neurosci Lett. 2012;530:97–102.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Pantazopoulos H, Woo T-UW, Lim MP, Lange N, Berretta S. Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia. Arch Gen Psychiatry. 2010;67:155–66.

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Pantazopoulos H, Markota M, Jaquet F, Ghosh D, Wallin A, Santos A, et al. Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala. Transl Psychiatry. 2015;5:e496.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Mauney SA, Athanas KM, Pantazopoulos H, Shaskan N, Passeri E, Berretta S, et al. Developmental pattern of perineuronal nets in the human prefrontal cortex and their deficit in schizophrenia. Biol Psychiatry. 2013;74:427–35.

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Pantazopoulos H, Boyer-Boiteau A, Holbrook EH, Jang W, Hahn C-G, Arnold SE, et al. Proteoglycan abnormalities in olfactory epithelium tissue from subjects diagnosed with schizophrenia. Schizophr Res. 2013;150:366–72.

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Enwright JF, Sanapala S, Foglio A, Berry R, Fish KN, Lewis DA. Reduced labeling of parvalbumin neurons and perineuronal nets in the dorsolateral prefrontal cortex of subjects with schizophrenia. Neuropsychopharmacology. 2016;41:2206–14.

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Alcaide J, Guirado R, Crespo C, Blasco-Ibáñez JM, Varea E, Sanjuan J, et al. Alterations of perineuronal nets in the dorsolateral prefrontal cortex of neuropsychiatric patients. Int J Bipolar Disord. 2019;7:24.

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Mueller TM, Yates SD, Haroutunian V, Meador-Woodruff JH. Altered fucosyltransferase expression in the superior temporal gyrus of elderly patients with schizophrenia. Schizophr Res. 2017;182:66–73.

    PubMed  PubMed Central  Google Scholar 

  44. 44.

    Kippe JM, Mueller TM, Haroutunian V, Meador-Woodruff JH. Abnormal N-acetylglucosaminyltransferase expression in prefrontal cortex in schizophrenia. Schizophr Res. 2015;166:219–24.

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Narayan S, Head SR, Gilmartin TJ, Dean B, Thomas EA. Evidence for disruption of sphingolipid metabolism in schizophrenia. J Neurosci Res. 2009;87:278–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Stanta JL, Saldova R, Struwe WB, Byrne JC, Leweke FM, Rothermund M, et al. Identification of N-glycosylation changes in the CSF and serum in patients with schizophrenia. J Proteome Res. 2010;9:4476–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Tsai G, Coyle JT. Glutamatergic mechanisms in schizophrenia. Annu Rev Pharm Toxicol. 2002;42:165–79.

    CAS  Google Scholar 

  48. 48.

    Howes O, McCutcheon R, Stone J. Glutamate and dopamine in schizophrenia: an update for the 21st century. J Psychopharmacol Oxf Engl. 2015;29:97–115.

    Google Scholar 

  49. 49.

    Buckner RL, DiNicola LM. The brain’s default network: updated anatomy, physiology and evolving insights. Nat Rev Neurosci. 2019;20:593–608.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Hunt MJ, Kopell NJ, Traub RD, Whittington MA. Aberrant network activity in schizophrenia. Trends Neurosci 2017;40:371–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Gao R, Penzes P. Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders. Curr Mol Med. 2015;15:146–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    The UniProt Consortium. UniProt: a worldwide hub of protein knowledge. Nucleic Acids Res. 2019;47:D506–15.

    Google Scholar 

  53. 53.

    Maupin KA, Liden D, Haab BB. The fine specificity of mannose-binding and galactose-binding lectins revealed using outlier motif analysis of glycan array data. Glycobiology 2012;22:160–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Mueller TM, Remedies CE, Haroutunian V, Meador-Woodruff JH. Abnormal subcellular localization of GABAA receptor subunits in schizophrenia brain. Transl Psychiatry. 2015;5:e612.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Schnaar RL, Gerardy-Schahn R, Hildebrandt H. Sialic acids in the brain: gangliosides and polysialic acid in nervous system development, stability, disease, and regeneration. Physiol Rev. 2014;94:461–518.

    PubMed  PubMed Central  Google Scholar 

  56. 56.

    Seki T, Arai Y. Distribution and possible roles of the highly polysialylated neural cell adhesion molecule (NCAM-H) in the developing and adult central nervous system. Neurosci Res. 1993;17:265–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Cox ET, Brennaman LH, Gable KL, Hamer RM, Glantz LA, Lamantia A-S, et al. Developmental regulation of neural cell adhesion molecule in human prefrontal cortex. Neuroscience. 2009;162:96–105.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Johnson CP, Fujimoto I, Rutishauser U, Leckband DE. Direct evidence that neural cell adhesion molecule (NCAM) polysialylation increases intermembrane repulsion and abrogates adhesion. J Biol Chem. 2005;280:137–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Nakata D, Troy FA. Degree of polymerization (DP) of polysialic acid (PolySia) on neural cell adhesion molecules (N-CAMs): development and application of a new strategy to accurately determine the DP of polysia chains on N-CAMS. J Biol Chem. 2005;280:38305–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Arai M, Yamada K, Toyota T, Obata N, Haga S, Yoshida Y, et al. Association between polymorphisms in the promoter region of the sialyltransferase 8B (SIAT8B) gene and schizophrenia. Biol Psychiatry. 2006;59:652–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Tao R, Li C, Zheng Y, Qin W, Zhang J, Li X, et al. Positive association between SIAT8B and schizophrenia in the Chinese Han population. Schizophr Res. 2007;90:108–14.

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Isomura R, Kitajima K, Sato C. Structural and functional impairments of polysialic acid by a mutated polysialyltransferase found in schizophrenia. J Biol Chem. 2011;286:21535–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Hildebrandt H, Mühlenhoff M, Oltmann-Norden I, Röckle I, Burkhardt H, Weinhold B, et al. Imbalance of neural cell adhesion molecule and polysialyltransferase alleles causes defective. Brain Connectivity Brain J Neurol. 2009;132:2831–8.

    Google Scholar 

  64. 64.

    Berretta S, Pantazopoulos H, Markota M, Brown C, Batzianouli ET. Losing the sugar coating: potential impact of perineuronal net abnormalities on interneurons in schizophrenia. Schizophr Res. 2015;167:18–27.

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Bitanihirwe BKY, Mauney SA, Woo T-UW. Weaving a net of neurobiological mechanisms in schizophrenia and unraveling the underlying pathophysiology. Biol Psychiatry. 2016;80:589–98.

    PubMed  PubMed Central  Google Scholar 

  66. 66.

    Bandtlow CE, Zimmermann DR. Proteoglycans in the developing brain: new conceptual insights for old proteins. Physiol Rev. 2000;80:1267–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Laabs TL, Wang H, Katagiri Y, McCann T, Fawcett JW, Geller HM. Inhibiting glycosaminoglycan chain polymerization decreases the inhibitory activity of astrocyte-derived chondroitin sulfate proteoglycans. J Neurosci Off. J Soc Neurosci. 2007;27:14494–501.

    CAS  Google Scholar 

  68. 68.

    Foscarin S, Raha-Chowdhury R, Fawcett JW, Kwok JCF. Brain ageing changes proteoglycan sulfation, rendering perineuronal nets more inhibitory. Aging 2017;9:1607–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Shah A, Lodge DJ. A loss of hippocampal perineuronal nets produces deficits in dopamine system function: relevance to the positive symptoms of schizophrenia. Transl Psychiatry. 2013;3:e215.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Pietersen CY, Mauney SA, Kim SS, Lim MP, Rooney RJ, Goldstein JM, et al. Molecular profiles of pyramidal neurons in the superior temporal cortex in schizophrenia. J Neurogenet. 2014;28:53–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Martins-de-Souza D, Gattaz WF, Schmitt A, Rewerts C, Marangoni S, Novello JC, et al. Alterations in oligodendrocyte proteins, calcium homeostasis and new potential markers in schizophrenia anterior temporal lobe are revealed by shotgun proteome analysis. J Neural Transm. 2009;116:275–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Wang Q, Wang C, Ji B, Zhou J, Yang C, Chen J. Hapln2 in neurological diseases and its potential as therapeutic target. Front Aging Neurosci. 2019;11:60.

    PubMed  PubMed Central  Google Scholar 

  73. 73.

    Takahashi N, Sakurai T, Bozdagi-Gunal O, Dorr NP, Moy J, Krug L, et al. Increased expression of receptor phosphotyrosine phosphatase-β/ζ is associated with molecular, cellular, behavioral and cognitive schizophrenia phenotypes. Transl Psychiatry. 2011;1:e8.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Mühleisen TW, Mattheisen M, Strohmaier J, Degenhardt F, Priebe L, Schultz CC, et al. Association between schizophrenia and common variation in neurocan (NCAN), a genetic risk factor for bipolar disorder. Schizophr Res 2012;138:69–73.

    PubMed  PubMed Central  Google Scholar 

  75. 75.

    Raum H, Dietsche B, Nagels A, Witt SH, Rietschel M, Kircher T, et al. A genome-wide supported psychiatric risk variant in NCAN influences brain function and cognitive performance in healthy subjects: NCAN genotype influences brain functioning. Hum Brain Mapp. 2015;36:378–90.

    PubMed  PubMed Central  Google Scholar 

  76. 76.

    Schultz CC, Mühleisen TW, Nenadic I, Koch K, Wagner G, Schachtzabel C, et al. Common variation in NCAN, a risk factor for bipolar disorder and schizophrenia, influences local cortical folding in schizophrenia. Psychol Med 2014;44:811–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Wang P, Cai J, Ni J, Zhang J, Tang W, Zhang C. The NCAN gene: schizophrenia susceptibility and cognitive dysfunction. Neuropsychiatr Dis Treat. 2016;12:2875–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Stahl EA, Breen G, Forstner AJ, McQuillin A, Ripke S, Trubetskoy V, et al. Genome-wide association study identifies 30 loci associated with bipolar disorder. Nat Genet. 2019;51:793–803.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Habl G, Schmitt A, Zink M, von Wilmsdorff M, Yeganeh-Doost P, Jatzko A, et al. Decreased reelin expression in the left prefrontal cortex (BA9) in chronic schizophrenia patients. Neuropsychobiology. 2012;66:57–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Impagnatiello F, Guidotti AR, Pesold C, Dwivedi Y, Caruncho H, Pisu MG, et al. A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc Natl Acad Sci USA. 1998;95:15718–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Eastwood SL, Law AJ, Everall IP, Harrison PJ. The axonal chemorepellant semaphorin 3A is increased in the cerebellum in schizophrenia and may contribute to its synaptic pathology. Mol Psychiatry 2003;8:148–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Walsh MT, Ryan M, Hillmann A, Condren R, Kenny D, Dinan T, et al. Elevated expression of integrin alpha(IIb) beta(IIIa) in drug-naïve, first-episode schizophrenic patients. Biol Psychiatry 2002;52:874–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Pantazopoulos H, Berretta S. In sickness and in health: perineuronal nets and synaptic plasticity in psychiatric disorders. Neural Plast 2016;2016:1–23.

    Google Scholar 

  84. 84.

    Beroun A, Mitra S, Michaluk P, Pijet B, Stefaniuk M, Kaczmarek L. MMPs in learning and memory and neuropsychiatric disorders. Cell Mol Life Sci. 2019;76:3207–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Mohamedi Y, Fontanil T, Cobo T, Cal S, Obaya AJ. New insights into ADAMTS metalloproteases in the central nervous system. Biomolecules 2020;10:403.

    CAS  Google Scholar 

  86. 86.

    Domenici E, Willé DR, Tozzi F, Prokopenko I, Miller S, McKeown A, et al. Plasma protein biomarkers for depression and schizophrenia by multi analyte profiling of case-control collections. PloS One. 2010;5:e9166.

    PubMed  PubMed Central  Google Scholar 

  87. 87.

    Yamamori H, Hashimoto R, Ishima T, Kishi F, Yasuda Y, Ohi K, et al. Plasma levels of mature brain-derived neurotrophic factor (BDNF) and matrix metalloproteinase-9 (MMP-9) in treatment-resistant schizophrenia treated with clozapine. Neurosci Lett. 2013;556:37–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Fukuda T, Hashimoto H, Okayasu N, Kameyama A, Onogi H, Nakagawasai O, et al. Alpha1,6-fucosyltransferase-deficient mice exhibit multiple behavioral abnormalities associated with a schizophrenia-like phenotype: importance of the balance between the dopamine and serotonin systems. J Biol Chem. 2011;286:18434–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Du J, Takeuchi H, Leonhard-Melief C, Shroyer KR, Dlugosz M, Haltiwanger RS, et al. O-fucosylation of thrombospondin type 1 repeats restricts epithelial to mesenchymal transition (EMT) and maintains epiblast pluripotency during mouse gastrulation. Dev Biol. 2010;346:25–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Berardinelli SJ, Haltiwanger RS. Analyzing the effects of O-fucosylation on secretion of ADAMTS proteins using cell-based assays. In: Apte SS, editor. ADAMTS Proteases, 2043, New York, NY: Springer New York; 2020. p. 25–43.

  91. 91.

    Enwright JF III, Huo Z, Arion D, Corradi JP, Tseng G, Lewis DA. Transcriptome alterations of prefrontal cortical parvalbumin neurons in schizophrenia. Mol Psychiatry. 2018;23:1606–13.

    CAS  Google Scholar 

  92. 92.

    Liu J, Shen L, Yang L, Hu S, Xu L, Wu S. High expression of β3GnT8 is associated with the metastatic potential of human glioma. Int J Mol Med. 2014;33:1459–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Lawrie SM, O’Donovan MC, Saks E, Burns T, Lieberman JA. Improving classification of psychoses. Lancet Psychiatry. 2016;3:367–74.

    PubMed  PubMed Central  Google Scholar 

  94. 94.

    Lawrie SM, O’Donovan MC, Saks E, Burns T, Lieberman JA. Towards diagnostic markers for the psychoses. Lancet Psychiatry. 2016;3:375–85.

    PubMed  PubMed Central  Google Scholar 

  95. 95.

    Chan MK, Tsang TM, Harris LW, Guest PC, Holmes E, Bahn S. Evidence for disease and antipsychotic medication effects in post-mortem brain from schizophrenia patients. Mol Psychiatry. 2011;16:1189–202.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Telford JE, Bones J, McManus C, Saldova R, Manning G, Doherty M, et al. Antipsychotic treatment of acute paranoid schizophrenia patients with olanzapine results in altered glycosylation of serum glycoproteins. J Proteome Res. 2012;11:3743–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Frasca A, Fumagalli F, Ter Horst J, Racagni G, Murphy KJ, Riva MA. Olanzapine, but not haloperidol, enhances PSA-NCAM immunoreactivity in rat prefrontal cortex. Int J Neuropsychopharmacol. 2008;11:591–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Abe C, Nishimura S, Mori A, Niimi Y, Yang Y, Hane M, et al. Chlorpromazine Increases the Expression of Polysialic Acid (PolySia) in Human Neuroblastoma Cells and Mouse Prefrontal Cortex. Int J Mol Sci. 2017;18:1123. https://doi.org/10.3390/ijms18061123.

  99. 99.

    Park DI, Štambuk J, Razdorov G, Pučić-Baković M, Martins-de-Souza D, Lauc G, et al. Blood plasma/IgG N-glycome biosignatures associated with major depressive disorder symptom severity and the antidepressant response. Sci Rep. 2018;8:179.

    PubMed  PubMed Central  Google Scholar 

  100. 100.

    Boeck C, Pfister S, Bürkle A, Vanhooren V, Libert C, Salinas-Manrique J, et al. Alterations of the serum N-glycan profile in female patients with major depressive disorder. J Affect Disord. 2018;234:139–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Yamagata H, Uchida S, Matsuo K, Harada K, Kobayashi A, Nakashima M, et al. Altered plasma protein glycosylation in a mouse model of depression and in patients with major depression. J Affect Disord. 2017. https://doi.org/10.1016/j.jad.2017.08.057.

  102. 102.

    Lin W, Vann DR, Doulias P-T, Wang T, Landesberg G, Li X, et al. Hepatic metal ion transporter ZIP8 regulates manganese homeostasis and manganese-dependent enzyme activity. J Clin Invest. 2017;127:2407–17.

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    Mealer RG, Jenkins BG, Chen C-Y, Daly MJ, Ge T, Lehoux S, et al. A schizophrenia risk locus alters brain metal transport and plasma glycosylation. bioRxiv.2019. https://doi.org/10.1101/757088.

  104. 104.

    Mueller TM, Meador-Woodruff JH. Post-translational protein modifications in schizophrenia. Npj Schizophr. 2020;6:5.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by a foundation grant from the Stanley Center for Psychiatric Research at the Broad Institute of Harvard/MIT (awarded to RGM).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Robert G. Mealer.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Williams, S.E., Mealer, R.G., Scolnick, E.M. et al. Aberrant glycosylation in schizophrenia: a review of 25 years of post-mortem brain studies. Mol Psychiatry 25, 3198–3207 (2020). https://doi.org/10.1038/s41380-020-0761-1

Download citation

Further reading

Search

Quick links