Analysis of the hydrolysis of peptides of functionally important regions of brain and glial neurotrophic factors by antibodies of patients with schizophrenia and other neuroimmune diseases

Analysis of the hydrolysis of peptides of functionally important regions of brain and glial neurotrophic factors by antibodies of patients with schizophrenia and other neuroimmune diseases

 

Authors

 

E.A. Ermakov

Institute of Chemical Biology and Fundamental Medicine of Siberian Branch of the Russian Academy of Sciences academician Lavrentyev Avenue 8, 630090, Novosibirsk, Russian Federation; Novosibirsk State University, Novosibirsk, Russian Federation

M.M. Melamud

Institute of Chemical Biology and Fundamental Medicine of Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation

G.A. Nevinsky

Institute of Chemical Biology and Fundamental Medicine of Siberian Branch of the Russian Academy of Sciences academician Lavrentyev Avenue 8, 630090, Novosibirsk, Russian Federation; Novosibirsk State University, Novosibirsk, Russian Federation

V.N. Buneva

Institute of Chemical Biology and Fundamental Medicine of Siberian Branch of the Russian Academy of Sciences academician Lavrentyev Avenue 8, 630090, Novosibirsk, Russian Federation; Novosibirsk State University, Novosibirsk, Russian Federation

 

https://doi.org/10.26617/1810-3111-2022-4(117)-5-13

 

Journal: Siberian Herald of Psychiatry and Addiction Psychiatry. 2022; 4 (117):  5-13.

 

Abstract

Background. In certain neuroimmune diseases, such as schizophrenia, multiple sclerosis (MS), and systemic lupus erythematosus (SLE), the nervous and immune systems are simultaneously affected to varying degrees. Some neuroimmune diseases are accompanied by a decrease in the concentration of brain (BDNF) and glial (GDNF)neurotrophic factors, which may be due to a decrease in the formation or their excessive destruction in blood. The destruction may be associated with the action of proteolytic enzymes. Hypothesis: Recently discovered catalytic antibodies with proteolytic properties can bind and hydrolyze BDNF and GDNF. Objective: to analyze the hydrolysis level of peptides of functionally important regions of BDNF and GDNF by antibodies of patients with schizophrenia, MS and SLE. Material and Methods. The total (n=112) study sample included healthy volunteers (n=30), patients with schizophrenia (n=20), SLE (n=32) and MS (n=30). IgG preparations were isolated by affinity chromatography from serum. To analyze the peptidase activity of IgG preparations, we used four fluorescently labeled peptides, which are fragments of functionally important regions of BDNF and GDNF involved in binding to specific receptors. The level of relative activity of IgG preparations was determined by thin layer chromatography. Results. It was shown that IgG preparations of patients effectively hydrolyzed all analyzed peptides. The level of hydrolysis of all four peptides by IgG preparations of patients with schizophrenia, MS and SLE was statistically significantly (p<0.0001) higher than healthy donors. IgG preparations of patients with schizophrenia had the highest activity in the hydrolysis of three peptides. Conclusion. The data obtained indicate that catalytic antibodies specifically recognizing and hydrolyzing BDNF and GDNF peptides are formed in the analyzed neuroimmune diseases. Antibody-dependent hydrolysis of functionally important regions of BDNF and GDNF might disrupt the functioning of these neurotrophic factors. However, the effects of catalytic antibodies need to be tested on full-sized molecules of neurotrophic factors.

 

Keywords: schizophrenia, multiple sclerosis, systemic lupus erythematosus, BDNF, GDNF, neurotrophic factor, catalytic antibodies.

 

Article (pdf)

 

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Materials  

For citation: Ermakov E.A., Melamud M.M., Nevinsky G.A., Buneva V.N. Analysis of the hydrolysis of peptides of functionally important regions of brain and glial neurotrophic factors by antibodies of patients with schizophrenia and other neuroimmune diseases.Siberian Herald of Psychiatry and Addiction Psychiatry.2022; 4 (117): 5-13. https://doi.org/10.26617/1810-3111-2022-4(117)-5-13

 

REFERENCES

  1. Benarroch EE. Brain-derived neurotrophic factor: Regulation, effects, and potential clinical relevance. Neurology. 2015 Apr 21;84(16):1693-704. doi: 10.1212/WNL.0000000000001507. Epub 2015 Mar 27. PMID: 25817841.
  2. Airaksinen MS, Saarma M. The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci. 2002 May;3(5):383-94. doi: 10.1038/nrn812. PMID: 11988777.
  3. Popova NK, Ilchibaeva TV, Naumenko VS. Neurotrophic factors (BDNF, GDNF) and the serotonergic system of the brain overview. Biochemistry (Mosc). 2017;82(3):449-459. doi: 10.1134/S0006297917030099 (in Russian).
  4. MikhalitskayaEV, LevchukLA. Brain neuroplasticity: brain-derived neurotrophic factor and protein kinase signaling pathways(literature review).Siberian Herald of Psychiatry and Addiction Psychiatry.2022; 3(116):44-53. https://doi.org/10.26617/1810-3111-2022-3(116)-44-53 (in Russian).
  5. Miranda M, Morici JF, Zanoni MB, Bekinschtein P. Brain-Derived Neurotrophic Factor: A Key Molecule for Memory in the Healthy and the Pathological Brain. Front Cell Neurosci. 2019 Aug 7;13:363. doi: 10.3389/fncel.2019.00363. PMID: 31440144; PMCID: PMC6692714.
  6. Shishkina TV, Vedunova MV, Mishchenko TA, Mukhina IV. The role of glial neurotrophic factor in the functioning of the nervous system. Modern Technologies in Medicine. 2015;7(4):211-220 (in Russian).
  7. Rocha SM, Cristovão AC, Campos FL, Fonseca CP, Baltazar G. Astrocyte-derived GDNF is a potent inhibitor of microglial activation. Neurobiol Dis. 2012 Sep;47(3):407-15. doi: 10.1016/j.nbd.2012.04.014. Epub 2012 May 3. PMID: 22579772.
  8. Ledda F, Paratcha G, Sandoval-Guzmán T, Ibáñez CF. GDNF and GFRalpha1 promote formation of neuronal synapses by ligand-induced cell adhesion. Nat Neurosci. 2007 Mar;10(3):293-300. doi: 10.1038/nn1855. Epub 2007 Feb 18. PMID: 17310246.
  9. Gudasheva TA, Povarnina P, Tarasiuk AV, Seredenin SB. Brain-derived neurotrophic factor and its small molecular weight mimetics. Pharmacokinetics and Pharmacodynamics. 2017;3:3-13 (in Russian).
  10. Ibáñez CF, Ilag LL, Murray-Rust J, Persson H. An extended surface of binding to Trk tyrosine kinase receptors in NGF and BDNF allows the engineering of a multifunctional pan-neurotrophin. EMBO J. 1993 Jun;12(6):2281-93. doi: 10.1002/j.1460-2075.1993.tb05882.x. PMID: 8508763; PMCID: PMC413458.
  11. Rydén M, Murray-Rust J, Glass D, Ilag LL, Trupp M, Yancopoulos GD, McDonald NQ, Ibáñez CF. Functional analysis of mutant neurotrophins deficient in low-affinity binding reveals a role for p75LNGFR in NT-4 signalling. EMBO J. 1995 May 1;14(9):1979-90. doi: 10.1002/j.1460-2075.1995.tb07190.x. PMID: 7744005; PMCID: PMC398297.
  12. Chen ZY, He ZY, He C, Lu CL, Wu XF. Human glial cell-line-derived neurotrophic factor: a structure-function analysis. Biochem Biophys Res Commun. 2000 Feb 24;268(3):692-6. doi: 10.1006/bbrc.2000.2196. PMID: 10679267.
  13. Parkash V, Leppänen VM, Virtanen H, Jurvansuu JM, Bespalov MM, Sidorova YA, Runeberg-Roos P, Saarma M, Goldman A. The structure of the glial cell line-derived neurotrophic factor-coreceptor complex: insights into RET signaling and heparin binding. J Biol Chem. 2008 Dec 12;283(50):35164-72. doi: 10.1074/jbc.M802543200. Epub 2008 Oct 8. PMID: 18845535; PMCID: PMC3259885.
  14. LevchukLA, VyalovaNM, MikhalitskayaEV, SemkinaAA, IvanovaSA. The role of BDNF in the pathogenesis of neurological and mental disorders. Modern Problems of Science and Education. 2018:6:58. doi: 10.17513/spno.28267 (in Russian).
  15. Wells E, Hacohen Y, Waldman A, Tillema JM, Soldatos A, Ances B, Benseler S, Bielekova B, Dale RC, Dalmau J, Gaillard W, Gorman M, Greenberg B, Hyslop A, Pardo CA, Tasker RC, Yeh EA, Bar-Or A, Pittock S, Vanderver A, Banwell B; attendees of the International Neuroimmune Meeting. Neuroimmune disorders of the central nervous system in children in the molecular era. Nat Rev Neurol. 2018 Jul;14(7):433-445. doi: 10.1038/s41582-018-0024-9. Erratum in: Nat Rev Neurol. 2018 Dec;14(12):749. PMID: 29925924.
  16. Ermakov EA, Melamud MM, Buneva VN, Ivanova SA. Immune System Abnormalities in Schizophrenia: An Integrative View and Translational Perspectives. Front Psychiatry. 2022 Apr 25;13:880568. doi: 10.3389/fpsyt.2022.880568. PMID: 35546942; PMCID: PMC9082498.
  17. LobachevaOA, VetluginaTP, KornetovaEG, SemkeAV. Immunoendocrine disorders in patients with schizophrenia during antipsychotic therapy. Russian Immunological Journal. 2019;13,2-1 (22):374-376DOI: 10.31857/S102872210006632-0(in Russian).
  18. Mednova IA, Boiko AS, Kornetova EG, Semke AV, Bokhan NA, Ivanova SA. Cytokines as Potential Biomarkers of Clinical Characteristics of Schizophrenia. Life. 2022;12:1972. https://doi.org/10.3390/life12121972.
  19. Koudriavtseva T, Mainero C. Neuroinflammation, neurodegeneration and regeneration in multiple sclerosis: intercorrelated manifestations of the immune response. Neural Regen Res. 2016 Nov;11(11):1727-1730. doi: 10.4103/1673-5374.194804. PMID: 28123401; PMCID: PMC5204213.
  20. Jeltsch-David H, Muller S. Neuropsychiatric systemic lupus erythematosus: pathogenesis and biomarkers. Nat Rev Neurol. 2014 Oct;10(10):579-96. doi: 10.1038/nrneurol.2014.148. Epub 2014 Sep 9. PMID: 25201240.
  21. Green MJ, Matheson SL, Shepherd A, Weickert CS, Carr VJ. Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis. Mol Psychiatry. 2011 Sep;16(9):960-72. doi: 10.1038/mp.2010.88. Epub 2010 Aug 24. PMID: 20733577.
  22. Karimi N, Ashourizadeh H, Akbarzadeh Pasha B, Haghshomar M, Jouzdani T, Shobeiri P, Teixeira AL, Rezaei N. Blood levels of brain-derived neurotrophic factor (BDNF) in people with multiple sclerosis (MS): A systematic review and meta-analysis. Mult Scler Relat Disord. 2022;65:103984. doi: 10.1016/j.msard.2022.103984
  23. Baba O, Kisaoglu H, Bilginer C, Ozkaya E, Kalyoncu M. Depression, anxiety, and sleep quality in childhood onset systemic lupus erythematosus and relationship with brain-derived neurotrophic factor. Lupus. 2022 Nov;31(13):1630-1638. doi: 10.1177/09612033221127901. Epub 2022 Sep 16. PMID: 36114161.
  24. Xiao W, Ye F, Liu C, Tang X, Li J, Dong H, Sha W, Zhang X. Cognitive impairment in first-episode drug-naïve patients with schizophrenia: Relationships with serum concentrations of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. Prog Neuropsychopharmacol Biol Psychiatry. 2017 Jun 2;76:163-168. doi: 10.1016/j.pnpbp.2017.03.013. Epub 2017 Mar 22. PMID: 28342945.
  25. Tunca Z, Kıvırcık Akdede B, Özerdem A, Alkın T, Polat S, Ceylan D, Bayın M, Cengizçetin Kocuk N, Şimşek S, Resmi H, Akan P. Diverse glial cell line-derived neurotrophic factor (GDNF) support between mania and schizophrenia: a comparative study in four major psychiatric disorders. Eur Psychiatry. 2015 Feb;30(2):198-204. doi: 10.1016/j.eurpsy.2014.11.003. Epub 2014 Dec 24. PMID: 25543333.
  26. Dias AFMP, Lanna CCD, Teixeira AL, Ferreira GA. Neurotrophic factors in systemic lupus erythematosus: markers of disease activity. Clin Exp Rheumatol. 2021 Nov-Dec;39(6):1451-1452. doi: 10.55563/clinexprheumatol/7ncg6y. Epub 2021 Jun 8. PMID: 34128803.
  27. Bauer JW, Baechler EC, Petri M, Batliwalla FM, Crawford D, Ortmann WA, Espe KJ, Li W, Patel DD, Gregersen PK, Behrens TW. Elevated serum levels of interferon-regulated chemokines are biomarkers for active human systemic lupus erythematosus. PLoS Med. 2006 Dec;3(12):e491. doi: 10.1371/journal.pmed.0030491. PMID: 17177599; PMCID: PMC1702557.
  28. Ermakov EA, Nevinsky GA, Buneva VN. Immunoglobulins with Non-Canonical Functions in Inflammatory and Autoimmune Disease States. Int J Mol Sci. 2020 Jul 29;21(15):5392. doi: 10.3390/ijms21155392. PMID: 32751323; PMCID: PMC7432551.
  29. Paul S, Volle DJ, Beach CM, Johnson DR, Powell MJ, Massey RJ. Catalytic hydrolysis of vasoactive intestinal peptide by human autoantibody. Science. 1989 Jun 9;244(4909):1158-62. doi: 10.1126/science.2727702. PMID: 2727702.
  30. Delgado M, Pozo D, Ganea D. The significance of vasoactive intestinal peptide in immunomodulation. Pharmacol Rev. 2004 Jun;56(2):249-90. doi: 10.1124/pr.56.2.7. PMID: 15169929.
  31. Ermakov EA, Parshukova DA, Nevinsky GA, Buneva VN. Natural Catalytic IgGs Hydrolyzing Histones in Schizophrenia: Are They the Link between Humoral Immunity and Inflammation? Int J Mol Sci. 2020 Sep 30;21(19):7238. doi: 10.3390/ijms21197238. PMID: 33008051; PMCID: PMC7582518.
  32. Parshukova D, Smirnova LP, Ermakov EA, Bokhan NA, Semke AV, Ivanova SA, Buneva VN, Nevinsky GA. Autoimmunity and immune system dysregulation in schizophrenia: IgGs from sera of patients hydrolyze myelin basic protein. J Mol Recognit. 2019 Feb;32(2):e2759. doi: 10.1002/jmr.2759. Epub 2018 Aug 15. PMID: 30112774.
  33. Howe HS, Leung BPL. Anti-Cytokine Autoantibodies in Systemic Lupus Erythematosus. Cells. 2019 Dec 27;9(1):72. doi: 10.3390/cells9010072. PMID: 31892200; PMCID: PMC7016754.
  34. Meager A, Wadhwa M. Detection of anti-cytokine antibodies and their clinical relevance. Expert Rev Clin Immunol. 2014 Aug;10(8):1029-47. doi: 10.1586/1744666X.2014.918848. Epub 2014 Jun 5. PMID: 24898469.