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REVIEW ARTICLE

Molecular mechanisms responsible for transglutaminase 2 involvement in the multiple sclerosis etiopathogenesis and its possible use as a neuroinflammation biomarker

Rosa Giacca1 ,  Maria Preziosi1 ,  Vittorio Gentile1*
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1 Department of Precision Medicine, School of Medicine and Surgery, University of Campania “Luigi Vanvitelli”, Naples , Italy
EJMO, 026170189 https://doi.org/10.36922/EJMO026170189
Received: 21 April 2026 | Revised: 2 August 2026 | Accepted: 24 August 2026 | Published online: 15 September 2026
(This article belongs to the Special Issue Biochemistry of neuroinflammation)
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
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Abstract

Introduction: Transglutaminase 2 (TG2) is a ubiquitous enzyme involved in extracellular matrix remodeling, cell adhesion, signal transduction, and modulation of immune responses. While its role in celiac disease is well established, increasing evidence supports its involvement in the pathogenesis of multiple sclerosis (MS).

Objectives: The objectives of this review are to describe the molecular mechanisms responsible for TG2 involvement in the multiple sclerosis etiopathogenesis and to evaluate its potential as a neuroinflammation biomarker.

Methods: The literature on the involvement of TG2 in MS was reviewed, with particular attention to its molecular mechanisms, expression in central and peripheral immune cells, association with disease activity and progression, and potential role as a biomarker of neuroinflammation.

Results: TG2 has been detected in monocytes and macrophages within demyelinating lesions, is induced in astrocytes by pro-inflammatory mediators, and is expressed in neurons and endothelial cells under neuroinflammatory conditions. Its localization in astrocytes within MS plaques further supports a role in sustaining neuroinflammation. Modulation of TG2 activity influences immune cell trafficking across the blood–brain barrier and regulates microglial and macrophage polarization. In patients with MS, altered TG2 expression and splicing isoforms in peripheral blood mononuclear cells are associated with disease activity, progression, and specific monocytic functional profiles. Preliminary findings in individuals with radiologically isolated syndrome suggest that peripheral TG2 expression may serve as an indicator of subclinical neuroinflammation.

Conclusion: Overall, TG2 emerges as a promising biomarker in MS, potentially complementing established neuroaxonal markers and improving phenotypic stratification. Further validation of its diagnostic and prognostic value will require large prospective studies integrating multi-omics approaches and advanced neuroimaging within a precision medicine framework.

 

Keywords
Transglutaminase 2
Multiple sclerosis
Biomarkers
Neuroinflammation
Peripheral blood mononuclear cells
Gene expression
Funding
None.
Conflict of interest
The authors declare they have no competing interests.
References
  1. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022;375(6578):296-301. doi: 10.1126/science.abj8222
  2. Montalban X, Lebrun-Frénay C, Oh J, et al. Diagnosis of multiple sclerosis: 2024 revisions of the McDonald criteria. Lancet Neurol. 2025;24(10):850-865. doi: 10.1016/S1474-4422(25)00270-4
  3. Folk JE. Mechanism and basis for specificity of transglutaminase-catalyzed epsilon-(gamma-glutamyl) lysine bond formation. Adv Enzymol Relat Areas Mol Biol. 1983;54:1-56. doi: 10.1002/9780470122990.ch1
  4. Lorand L, Graham RM. Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol. 2003;4(2):140-156. doi: 10.1038/nrm1014
  5. Lee J, Kim YS, Choi DH, et al. Transglutaminase 2 induces nuclear factor-kappaB activation via a novel pathway in BV-2 microglia. J Biol Chem. 2004;279(51):53725-53735. doi: 10.1074/jbc.M407627200
  6. Liu J, Mouradian MM. Pathogenetic Contributions and Therapeutic Implications of Transglutaminase 2 in Neurodegenerative Diseases. Int J Mol Sci. 2024;25(4):2364. doi: 10.3390/ijms25042364
  7. Espitia Pinzón N, Brevé JJP, Bol JGJM, Drukarch B, Baron W, van Dam AM. Tissue transglutaminase in astrocytes is enhanced by inflammatory mediators and is involved in the formation of fibronectin fibril-like structures. J Neuroinflammation. 2017;14(1):260. doi: 10.1186/s12974-017-1031-2
  8. Parente A, Gatta NG, Battipaglia M, Giuliano A, Capolongo F, Gentile V. Possible roles of the transglutaminases in the molecular mechanisms responsible for human neurodegenerative diseases. SunText Rev Neurosci Psychol. 2020;1(2):114. doi: 10.51737/2766-4503.2020.014
  9. Nurminskaya MV, Belkin AM. Cellular functions of tissue transglutaminase. In: Jeon JW, ed. International Review of Cell and Molecular Biology. Vol 294. Amsterdam, Netherlands: Elsevier; 2012:1-97. doi: 10.1016/B978-0-12-394305-7.00001-X
  10. Jeitner TM, Pinto JT, Krasnikov BF, Horswill M, Cooper AJ. Transglutaminases and neurodegeneration. J Neurochem. 2009;109(Suppl 1):160-166. doi: 10.1111/j.1471-4159.2009.05843.x
  11. Hasegawa G, Suwa M, Ichikawa Y, et al. A novel function of tissue-type transglutaminase: protein disulphide isomerase. Biochem J. 2003;373(3):793-803. doi: 10.1042/BJ20021084
  12. Nakaoka H, Perez DM, Baek KJ, et al. Gh: a GTP-binding protein with transglutaminase activity and receptor signaling function. Science. 1994;264(5165):1593-1596. doi: 10.1126/science.7911253
  13. Gentile V, Porta R, Chiosi E, et al. tTGase/G alpha h protein expression inhibits adenylate cyclase activity in Balb-C 3T3 fibroblasts membranes. Biochim Biophys Acta. 1997;1357(1):115-122. doi: 10.1016/s0167-4889(97)00024-4
  14. Lahav J, Karniel E, Bagoly Z, Sheptovitsky V, Dardik R, Inbal A. Coagulation factor XIII serves as protein disulfide isomerase. Thromb Haemost. 2009;101(5):840-844. doi: 10.1160/TH08-09-0605
  15. Mishra S, Murphy LJ. Tissue transglutaminase has intrinsic kinase activity: identification of transglutaminase 2 as an insulin-like growth factor-binding protein-3 kinase. J Biol Chem. 2004;279(23):23863-23868. doi: 10.1074/jbc.M311919200
  16. Begg GE, Carrington L, Stokes PH, et al. Mechanism of allosteric regulation of transglutaminase 2 by GTP. Proc Natl Acad Sci USA. 2006;103(52):19683-19688. doi: 10.1073/pnas.0609283103
  17. Király R, Csosz E, Kurtán T, et al. Functional significance of five noncanonical Ca2+-binding sites of human transglutaminase 2 characterized by site-directed mutagenesis. FEBS J. 2009;276(23):7083-7096. doi: 10.1111/j.1742-4658.2009.07420.x
  18. Fesus L, Piacentini M. Transglutaminase 2: an enigmatic enzyme with diverse functions. Trends Biochem Sci. 2002;27(10):534-539. doi: 10.1016/s0968-0004(02)02182-5
  19. Mehta K, Kumar A, Kim HI. Transglutaminase 2: A multi-tasking protein in the complex circuitry of inflammation and cancer. Biochem Pharmacol. 2010;80(12):1921-1929. doi: 10.1016/j.bcp.2010.06.029
  20. Liu S, Cerione RA, Clardy J. Structural basis for the guanine nucleotide-binding activity of tissue transglutaminase and its regulation of transamidation activity. Proc Natl Acad Sci USA. 2002;99(5):2743-2747. doi: 10.1073/pnas.042454899
  21. Pinkas DM, Strop P, Brunger AT, Khosla C. Transglutaminase 2 undergoes a large conformational change upon activation. PLoS Biol. 2007;5(12):e327. doi: 10.1371/journal.pbio.0050327
  22. Stamnaes J, Pinkas DM, Fleckenstein B, Khosla C, Sollid LM. Redox regulation of transglutaminase 2 activity. J Biol Chem. 2010;285(33):25402-25409. doi: 10.1074/jbc.M109.097162
  23. Jin X, Stamnaes J, Klöck C, DiRaimondo TR, Sollid LM, Khosla C. Activation of extracellular transglutaminase 2 by thioredoxin. J Biol Chem. 2011;286(43):37866-37873. doi: 10.1074/jbc.M111.287490
  24. Johnson K, Hashimoto S, Lotz M, Pritzker K, Terkeltaub R. Interleukin-1 induces pro-mineralizing activity of cartilage tissue transglutaminase and factor XIIIa. Am J Pathol. 2001;159(1):149-163. doi: 10.1016/S0002-9440(10)61682-3
  25. Oh K, Ko E, Kim HS, et al. Transglutaminase 2 facilitates the distant hematogenous metastasis of breast cancer by modulating interleukin-6 in cancer cells. Breast Cancer Res. 2011;13(5):R96. doi: 10.1186/bcr3034
  26. Kuo TF, Tatsukawa H, Matsuura T, Nagatsuma K, Hirose S, Kojima S. Free fatty acids induce transglutaminase 2-dependent apoptosis in hepatocytes via ER stress-stimulated PERK pathways. J Cell Physiol. 2012;227(3):1130-1137. doi: 10.1002/jcp.22833
  27. Currò M, Condello S, Caccamo D, Ferlazzo N, Parisi G, Ientile R. Homocysteine-induced toxicity increases TG2 expression in Neuro2a cells. Amino Acids. 2009;36(4):725-730. doi: 10.1007/s00726-008-0122-x
  28. Telci D, Collighan RJ, Basaga H, Griffin M. Increased TG2 expression can result in induction of transforming growth factor beta1, causing increased synthesis and deposition of matrix proteins, which can be regulated by nitric oxide. J Biol Chem. 2009;284(43):29547-29558. doi: 10.1074/jbc.M109.041806
  29. Shweke N, Boulos N, Jouanneau C, et al. Tissue transglutaminase contributes to interstitial renal fibrosis by favoring accumulation of fibrillar collagen through TGF-beta activation and cell infiltration. Am J Pathol. 2008;173(3):631-642. doi: 10.2353/ajpath.2008.080025
  30. Kim SY. Transglutaminase 2 in inflammation. Front Biosci. 2006;11(3):3026-3035. doi: 10.2741/2030
  31. Cellura D, Pickard K, Quaratino S, et al. miR-19-Mediated Inhibition of Transglutaminase-2 Leads to Enhanced Invasion and Metastasis in Colorectal Cancer. Mol Cancer Res. 2015;13(7):1095-1105. doi: 10.1158/1541-7786.MCR-14-0466
  32. Lai TS, Liu Y, Li W, Greenberg CS. Identification of two GTP-independent alternatively spliced forms of tissue transglutaminase in human leukocytes, vascular smooth muscle, and endothelial cells. FASEB J. 2007;21(14):4131-4143. doi: 10.1096/fj.06-7598com
  33. Bianchi N, Beninati S, Bergamini CM. Spotlight on the transglutaminase 2 gene: a focus on genomic and transcriptional aspects. Biochem J. 2018;475(9):1643-1667. doi: 10.1042/BCJ20170601
  34. Tee AEL, Marshall GM, Liu PY, et al. Opposing effects of two tissue transglutaminase protein isoforms in neuroblastoma cell differentiation. J Biol Chem. 2010;285(6):3561-3567. doi: 10.1074/jbc.M109.053041
  35. Antonyak MA, Jansen JM, Miller AM, Ly TK, Endo M, Cerione RA. Two isoforms of tissue transglutaminase mediate opposing cellular fates. Proc Natl Acad Sci USA. 2006;103(49):18609-18614. doi: 10.1073/pnas.0604844103
  36. Phatak VM, Croft SM, Rameshaiah Setty SG, et al. Expression of transglutaminase-2 isoforms in normal human tissues and cancer cell lines: dysregulation of alternative splicing in cancer. Amino Acids. 2013;44(1):33-44. doi: 10.1007/s00726-011-1127-4
  37. Arbildi P, Calvo F, Macías V, Rodríguez-Camejo C, Sóñora C, Hernández A. Study of tissue transglutaminase spliced variants expressed in THP-1 derived macrophages exhibiting distinct functional phenotypes. Immunobiology. 2023;228(6):152752. doi: 10.1016/j.imbio.2023.152752
  38. Sestito C, Brevé JJP, van Eggermond MCJA, et al. Monocyte-derived tissue transglutaminase in multiple sclerosis patients: reflecting an anti-inflammatory status and function of the cells? J Neuroinflammation. 2017;14(1):257. doi: 10.1186/s12974-017-1035-y
  39. Iismaa SE, Mearns BM, Lorand L, Graham RM. Transglutaminases and disease: lessons from genetically engineered mouse models and inherited disorders. Physiol Rev. 2009;89(3):991-1023. doi: 10.1152/physrev.00044.2008
  40. Furini G, Schroeder N, Huang L, et al. Proteomic Profiling Reveals the Transglutaminase-2 Externalization Pathway in Kidneys after Unilateral Ureteric Obstruction. J Am Soc Nephrol. 2018;29(3):880-905. doi: 10.1681/ASN.2017050479
  41. Griffin M, Casadio R, Bergamini CM. Transglutaminases: nature's biological glues. Biochem J. 2002;368(2):377-396. doi: 10.1042/BJ20021234
  42. Gentile V, Thomazy V, Piacentini M, Fesus L, Davies PJ. Expression of tissue transglutaminase in Balb-C 3T3 fibroblasts: effects on cellular morphology and adhesion. J Cell Biol. 1992;119(2):463-474. doi: 10.1083/jcb.119.2.463
  43. Melino G, Annicchiarico-Petruzzelli M, Piredda L, et al. Tissue transglutaminase and apoptosis: sense and antisense transfection studies with human neuroblastoma cells. Mol Cell Biol. 1994;14(10):6584-6596. doi: 10.1128/mcb.14.10.6584-6596.1994
  44. Milakovic T, Tucholski J, McCoy E, Johnson GV. Intracellular localization and activity state of tissue transglutaminase differentially impacts cell death. J Biol Chem. 2004;279(10):8715-8722. doi: 10.1074/jbc.M308479200
  45. Feng JF, Rhee SG, Im MJ. Evidence that phospholipase δ1 is the effector in the Gh (transglutaminase II)-mediated signaling. J Biol Chem. 1996;271(28):16451-16454. doi: 10.1074/jbc.271.28.16451
  46. Sarang Z, Molnár P, Németh T, et al. Tissue transglutaminase (TG2) acting as G protein protects hepatocytes against Fas-mediated cell death in mice. Hepatology. 2005;42(3):578-587. doi: 10.1002/hep.20812
  47. Lai TS, Lin CJ, Wu YT, Wu CJ. Tissue transglutaminase (TG2) and mitochondrial function and dysfunction. Front Biosci (Landmark Ed). 2017;22(7):1114-1137. doi: 10.2741/4536
  48. Cho SY, Lee JH, Bae HD, et al. Transglutaminase 2 inhibits apoptosis induced by calcium-overload through down-regulation of Bax. Exp Mol Med. 2010;42(9):639-650. doi: 10.3858/emm.2010.42.9.063
  49. Zemskov EA, Loukinova E, Mikhailenko I, Coleman RA, Strickland DK, Belkin AM. Regulation of platelet-derived growth factor receptor function by integrin-associated cell surface transglutaminase. J Biol Chem. 2009;284(24):16693-16703. doi: 10.1074/jbc.M109.010769
  50. Town T, Nikolic V, Tan J. The microglial "activation" continuum: from innate to adaptive responses. J Neuroinflammation. 2005;2:24. doi: 10.1186/1742-2094-2-24
  51. Tuppo EE, Arias HR. The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol. 2005;37(2):289-305. doi: 10.1016/j.biocel.2004.07.009
  52. Lesort M, Chun W, Johnson GVW, Ferrante RJ. Tissue transglutaminase is increased in Huntington's disease brain. J Neurochem. 1999;73(5):2018-2027. doi: 10.1046/j.1471-4159.1999.02018.x
  53. Mastroberardino PG, Iannicola C, Nardacci R, et al. 'Tissue' transglutaminase ablation reduces neuronal death and prolongs survival in a mouse model of Huntington's disease. Cell Death Differ. 2002;9(9):873-880. doi: 10.1038/sj.cdd.4401093
  54. Bailey CD, Johnson GVW. The protective effects of cystamine in the R6/2 Huntington's disease mouse involve mechanisms other than the inhibition of tissue transglutaminase. Neurobiol Aging. 2006;27(6):871-879. doi: 10.1016/j.neurobiolaging.2005.04.001
  55. Citron BA, SantaCruz KS, Davies PJ, Festoff BW. Intron-exon swapping of transglutaminase mRNA and neuronal tau aggregation in Alzheimer's disease. J Biol Chem. 2001;276(5):3295-3301. doi: 10.1074/jbc.M004776200
  56. Johnson GVW, Cox TM, Lockhart JP, Zinnerman MD, Miller ML, Powers RE. Transglutaminase activity is increased in Alzheimer's disease brain. Brain Res. 1997;751(2):323-329. doi: 10.1016/s0006-8993(96)01431-x
  57. Junn E, Ronchetti RD, Quezado MM, Kim SY, Mouradian MM. Tissue transglutaminase-induced aggregation of alpha-synuclein: Implications for Lewy body formation in Parkinson's disease and dementia with Lewy bodies. Proc Natl Acad Sci USA. 2003;100(4):2047-2052. doi: 10.1073/pnas.0438021100
  58. Citron BA, Suo Z, SantaCruz K, Davies PJ, Qin F, Festoff BW. Protein crosslinking, tissue transglutaminase, alternative splicing and neurodegeneration. Neurochem Int. 2002;40(1):69-78. doi: 10.1016/s0197-0186(01)00062-6
  59. Zemaitaitis MO, Kim SY, Halverson RA, Troncoso JC, Lee JM, Muma NA. Transglutaminase activity, protein, and mRNA expression are increased in progressive supranuclear palsy. J Neuropathol Exp Neurol. 2003;62(2):173-184. doi: 10.1093/jnen/62.2.173
  60. Lesort M, Tucholski J, Miller ML, Johnson GVW. Tissue transglutaminase: a possible role in neurodegenerative diseases. Prog Neurobiol. 2000;61(5):439-463. doi: 10.1016/s0301-0082(99)00052-0
  61. Selkoe DJ, Abraham C, Ihara Y. Brain transglutaminase: in vitro crosslinking of human neurofilament proteins into insoluble polymers. Proc Natl Acad Sci USA. 1982;79(19):6070-6074. doi: 10.1073/pnas.79.19.6070
  62. Grierson AJ, Johnson GVW, Miller CC. Three different human tau isoforms and rat neurofilament light, middle and heavy chain proteins are cellular substrates for transglutaminase. Neurosci Lett. 2001;298(1):9-12. doi: 10.1016/s0304-3940(00)01714-6
  63. Singer SM, Zainelli GM, Norlund MA, Lee JM, Muma NA. Transglutaminase bonds in neurofibrillary tangles and paired helical filament tau early in Alzheimer's disease. Neurochem Int. 2002;40(1):17-30. doi: 10.1016/s0197-0186(01)00061-4
  64. Halverson RA, Lewis J, Frausto S, Hutton M, Muma NA. Tau protein is cross-linked by transglutaminase in P301L tau transgenic mice. J Neurosci. 2005;25(5):1226-1233. doi: 10.1523/JNEUROSCI.3263-04.2005
  65. Jeitner TM, Matson WR, Folk JE, Blass JP, Cooper AJ. Increased levels of gamma-glutamylamines in Huntington disease CSF. J Neurochem. 2008;106(1):37-44. doi: 10.1111/j.1471-4159.2008.05350.x
  66. Dudek SM, Johnson GVW. Transglutaminase facilitates the formation of polymers of the beta-amyloid peptide. Brain Res. 1994;651(1-2):129-133. doi: 10.1016/0006-8993(94)90688-2
  67. Hartley DM, Zhao C, Speier AC, et al. Transglutaminase induces protofibril-like amyloid beta-protein assemblies that are protease-resistant and inhibit long-term potentiation. J Biol Chem. 2008;283(24):16790-16800. doi: 10.1074/jbc.M802215200
  68. Giri R, Shen Y, Stins M, et al. β-amyloid-induced migration of monocytes across human brain endothelial cells involves RAGE and PECAM-1. Am J Physiol Cell Physiol. 2000;279(6):C1772-C1781. doi: 10.1152/ajpcell.2000.279.6.C1772
  69. Le Y, Gong W, Tiffany HL, et al. Amyloid β42 activates a G-protein-coupled chemoattractant receptor, FPR-like-1. J Neurosci. 2001;21(2):RC123. doi: 10.1523/JNEUROSCI.21-02-j0003.2001
  70. Yan SD, Chen X, Fu J, et al. RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease. Nature. 1996;382(6593):685-691. doi: 10.1038/382685a0
  71. Fiala M, Zhang L, Gan X, et al. Amyloid-β induces chemokine secretion and monocyte migration across a human blood--brain barrier model. Mol Med. 1998;4(7):480-489.
  72. Yates SL, Burgess LH, Kocsis-Angle J, et al. Amyloid β and amylin fibrils induce increases in proinflammatory cytokine and chemokine production by THP-1 cells and murine microglia. J Neurochem. 2000;74(3):1017-1025. doi: 10.1046/j.1471-4159.2000.0741017.x
  73. Currò M, Gangemi C, Giunta ML, et al. Transglutaminase 2 is involved in amyloid-beta1-42-induced pro-inflammatory activation via AP1/JNK signalling pathways in THP-1 monocytes. Amino Acids. 2017;49(3):659-669. doi: 10.1007/s00726-016-2366-1
  74. Gatta NG, Parente A, Guida F, Maione S, Gentile V. Neutonutraceuticals modulate lipopolysaccharide- or amyloid-β1-42-induced transglutaminase 2 overexpression in mouse microglial cells. Appl Sci. 2021;11(12):5718. doi: 10.3390/app11125718
  75. Currò M, Ferlazzo N, Condello S, Caccamo D, Ientile R. Transglutaminase 2 silencing reduced the beta-amyloid-effects on the activation of human THP-1 cells. Amino Acids. 2010;39(5):1427-1433. doi: 10.1007/s00726-010-0605-4
  76. Hou Y, Xiao X, Yu W, Qi S. Propofol Suppresses Microglia Inflammation by Targeting TGM2/NF-κB Signaling. J Immunol Res. 2021;2021:4754454. doi: 10.1155/2021/4754454
  77. Zemaitaitis MO, Lee JM, Troncoso JC, Muma NA. Transglutaminase-induced cross-linking of tau proteins in progressive supranuclear palsy. J Neuropathol Exp Neurol. 2000;59(11):983-989. doi: 10.1093/jnen/59.11.983
  78. Gentile V, Sepe C, Calvani M, et al. Tissue transglutaminase-catalyzed formation of high-molecular-weight aggregates in vitro is favored with long polyglutamine domains: a possible mechanism contributing to CAG-triplet diseases. Arch Biochem Biophys. 1998;352(2):314-321. doi: 10.1006/abbi.1998.0592
  79. Kahlem P, Green H, Djian P. Transglutaminase action imitates Huntington's disease: selective polymerization of Huntingtin containing expanded polyglutamine. Mol Cell. 1998;1(4):595-601. doi: 10.1016/s1097-2765(00)80059-3
  80. Karpuj MV, Garren H, Slunt H, et al. Transglutaminase aggregates huntingtin into nonamyloidogenic polymers, and its enzymatic activity increases in Huntington's disease brain nuclei. Proc Natl Acad Sci USA. 1999;96(13):7388-7393. doi: 10.1073/pnas.96.13.7388
  81. Segers-Nolten IM, Wilhelmus MM, Veldhuis G, van Rooijen BD, Drukarch B, Subramaniam V. Tissue transglutaminase modulates alpha-synuclein oligomerization. Protein Sci. 2008;17(8):1395-1402. doi: 10.1110/ps.036103.108
  82. Lai TS, Tucker T, Burke JR, Strittmatter WJ, Greenberg CS. Effect of tissue transglutaminase on the solubility of proteins containing expanded polyglutamine repeats. J Neurochem. 2004;88(5):1253-1260. doi: 10.1046/j.1471-4159.2003.02249.x
  83. Sestito C, Brevé JJP, Bol JGJM, Wilhelmus MMM, Drukarch B, van Dam AM. Tissue Transglutaminase contributes to myelin phagocytosis in interleukin-4-treated human monocyte-derived macrophages. Cytokine. 2020;128:155024. doi: 10.1016/j.cyto.2020.155024
  84. Sun H, Kaartinen MT. Transglutaminases in Monocytes and Macrophages. Med Sci. 2018;6(4):115. doi: 10.3390/medsci6040115
  85. Ientile R, Currò M, Caccamo D. Transglutaminase 2 and neuroinflammation. Amino Acids. 2015;47(1):19-26. doi: 10.1007/s00726-014-1864-2
  86. Pearse DD, Otero PA, Diaz A, Pan X, Ghosh M. Neuronal and Endothelial Transglutaminase-2 Expression during Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis. Neuroscience. 2021;461:140-154. doi: 10.1016/j.neuroscience.2020.11.034
  87. Espitia Pinzon N, Sanz-Morello B, Brevé JJ, et al. Astrocyte-derived tissue Transglutaminase affects fibronectin deposition, but not aggregation, during cuprizone-induced demyelination. Sci Rep. 2017;7:40995. doi: 10.1038/srep40995
  88. Chrobok NL, Bol JGJM, Jongenelen CA, et al. Characterization of Transglutaminase 2 activity inhibitors in monocytes in vitro and their effect in a mouse model for multiple sclerosis. PLoS One. 2018;13(4):e0196433. doi: 10.1371/journal.pone.0196433
  89. Chrobok NL, Bol JGJM, Wilhelmus MMM, Drukarch B, van Dam AM. Tissue Transglutaminase Appears in Monocytes and Macrophages but Not in Lymphocytes in White Matter Multiple Sclerosis Lesions. J Neuropathol Exp Neurol. 2019;78(6):492-500. doi: 10.1093/jnen/nlz030
  90. Beckouche N, Bignon M, Lelarge V, et al. The interaction of heparan sulfate proteoglycans with endothelial transglutaminase-2 limits VEGF165-induced angiogenesis. Sci Signal. 2015;8(385):ra70. doi: 10.1126/scisignal.aaa0963
  91. Elahi A, Emerson J, Rudlong J, et al. Deletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury. Cells. 2021;10(11):2942. doi: 10.3390/cells10112942
  92. Monteagudo A, Feola J, Natola H, Ji C, Pröschel C, Johnson GVW. Depletion of astrocytic transglutaminase 2 improves injury outcomes. Mol Cell Neurosci. 2018;92:128-136. doi: 10.1016/j.mcn.2018.06.007
  93. Lau LW, Keough MB, Haylock-Jacobs S, et al. Chondroitin sulfate proteoglycans in demyelinated lesions impair remyelination. Ann Neurol. 2012;72(3):419-432. doi: 10.1002/ana.23599
  94. Pearse DD, Hefley AB, Morales AA, Ghosh M. Comparative Profiling of TG2 and Its Effectors in Human Relapsing Remitting and Progressive Multiple Sclerosis. Biomedicines. 2022;10(6):1241. doi: 10.3390/biomedicines10061241
  95. Sestito C, Leurs CE, Steenwijk MD, et al. Tissue Transglutaminase Expression Associates With Progression of Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2021;8(4):e998. doi: 10.1212/NXI.0000000000000998
  96. Sestito C, Brevé JJP, Killestein J, et al. Differential Expression of Tissue Transglutaminase Splice Variants in Peripheral Blood Mononuclear Cells of Primary Progressive Multiple Sclerosis Patients. Med Sci. 2018;6(4):108. doi: 10.3390/medsci6040108
  97. Giacca R, Conte M, d'Ambrosio A, et al. Use of Transglutaminase 2 mRNA expression in peripheral blood mononuclear cells in patients with Radiologically Isolated Syndrome as a neuroinflammation biomarker: A preliminary study. AIMS Neurosci. 2025;12(2):284-290. doi: 10.3934/Neuroscience.2025015
  98. van Strien ME, de Vries HE, Chrobok NL, et al. Tissue Transglutaminase contributes to experimental multiple sclerosis pathogenesis and clinical outcome by promoting macrophage migration. Brain Behav Immun. 2015;50:141-154. doi: 10.1016/j.bbi.2015.06.023
  99. Andersson M, Alvarez-Cermeño J, Bernardi G, et al. Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report. J Neurol Neurosurg Psychiatry. 1994;57(8):897-902. doi: 10.1136/jnnp.57.8.897
  100. Zeman D, Hradilek P, Kusnierova P, et al. Oligoclonal free light chains in cerebrospinal fluid as markers of intrathecal inflammation. Comparison with oligoclonal IgG. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2015;159(1):104-113. doi: 10.5507/bp.2014.058
  101. Hegen H, Zinganell A, Auer M, Deisenhammer F. The clinical significance of single or double bands in cerebrospinal fluid isoelectric focusing. A retrospective study and systematic review. PLoS One. 2019;14(4):e0215410. doi: 10.1371/journal.pone.0215410
  102. Fortini AS, Sanders EL, Weinshenker BG, Katzmann JA. Cerebrospinal Fluid Oligoclonal Bands in the Diagnosis of Multiple Sclerosis. Am J Clin Pathol. 2003;120(5):672-675. doi: 10.1309/y5vff2uaw0rk5w63
  103. Deisenhammer F, Zetterberg H, Fitzner B, Zettl UK. The Cerebrospinal Fluid in Multiple Sclerosis. Front Immunol. 2019;10:726. doi: 10.3389/fimmu.2019.00726
  104. Hassan-Smith G, Durant L, Tsentemeidou A, et al. High sensitivity and specificity of elevated cerebrospinal fluid kappa free light chains in suspected multiple sclerosis. J Neuroimmunol. 2014;276(1-2):175-179. doi: 10.1016/j.jneuroim.2014.08.003
  105. Nazarov V, Makshakov G, Kalinin I, et al. Concentrations of immunoglobulin free light chains in cerebrospinal fluid predict increased level of brain atrophy in multiple sclerosis. Immunol Res. 2018;66(6):761-767. doi: 10.1007/s12026-018-9058-8
  106. Hegen H, Auer M, Zeileis A, Deisenhammer F. Upper reference limits for cerebrospinal fluid total protein and albumin quotient based on a large cohort of control patients: implications for increased clinical specificity. Clin Chem Lab Med. 2016;54(2):285-292. doi: 10.1515/cclm-2015-0253
  107. Ramsden DB. Multiple sclerosis: assay of free immunoglobulin light chains. Ann Clin Biochem. 2017;54(1):5-13. doi: 10.1177/0004563216652175
  108. Dutta R, Trapp BD. Pathogenesis of axonal and neuronal damage in multiple sclerosis. Neurology. 2007;68(22 Suppl 3):S22-S54. doi: 10.1212/01.wnl.0000275229.13012.32
  109. Puthenparampil M, Altinier S, Stropparo E, et al. Intrathecal K free light chain synthesis in multiple sclerosis at clinical onset associates with local IgG production and improves the diagnostic value of cerebrospinal fluid examination. Mult Scler Relat Disord. 2018;25:241-245. doi: 10.1016/j.msard.2018.08.002
  110. Sato DK, Callegaro D, Lana-Peixoto MA, et al. Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology. 2014;82(6):474-481. doi: 10.1212/WNL.0000000000000101
  111. Waters P, Woodhall M, O'Connor KC, et al. MOG cell-based assay detects non-MS patients with inflammatory neurologic disease. Neurol Neuroimmunol Neuroinflamm. 2015;2(3):e89. doi: 10.1212/NXI.0000000000000089
  112. Keillor JW, Apperley KY, Akbar A. Inhibitors of tissue transglutaminase. Trends Pharmacol Sci. 2015;36(1):32-40. doi: 10.1016/j.tips.2014.10.014
  113. Kargbo RB. Development and Utilization of Novel Transglutaminase 2 Inhibitors for Potential Treatment of Autoimmune Disease and Gastrointestinal Disorder. ACS Med Chem Lett. 2023;14(11):1496-1497. doi: 10.1021/acsmedchemlett.3c00443
  114. Siegel M, Khosla C. Transglutaminase 2 inhibitors and their therapeutic role in disease states. Pharmacol Ther. 2007;115(2):232-245. doi: 10.1016/j.pharmthera.2007.05.003
  115. Cano A, Sánchez-López E, Ettcheto M, et al. Current advances in the development of novel polymeric nanoparticles for the treatment of neurodegenerative diseases. Nanomedicine. 2020;15(12):1239-1261. doi: 10.2217/nnm-2019-0443
  116. Lamptey RNL, Chaulagain B, Trivedi R, Gothwal A, Layek B, Singh J. A Review of the Common Neurodegenerative Disorders: Current Therapeutic Approaches and the Potential Role of Nanotherapeutics. Int J Mol Sci. 2022;23(3):1851. doi: 10.3390/ijms23031851
  117. Mistretta M, Farini A, Torrente Y, Villa C. Multifaceted nanoparticles: emerging mechanisms and therapies in neurodegenerative diseases. Brain. 2023;146(6):2227-2240. doi: 10.1093/brain/awad014
  118. Parente A, Giacca R, Arena R, et al. Amyloid-β-Induced Transglutaminase 2 Expression and Activities are Modulated by 2-Pentadecyl-2-Oxazoline in Mouse and Human Microglial Cell Lines. Curr Alzheimer Res. 2023;20(4):289-300. doi: 10.2174/1567205020666230804100831
  119. Gatta NG, Cammarota G, Iannaccone M, Serretiello E, Gentile V. Curcumin (Diferulolylmethane) Reduces Transglutaminase 2 Overexpression Induced by Retinoic Acid in Human Nervous Cell Lines. Neuroimmunomodulation. 2016;23(3):188-193. doi: 10.1159/000448998
  120. Wang D, Li SP, Fu JS, Zhang S, Bai L, Guo L. Resveratrol defends blood-brain barrier integrity in experimental autoimmune encephalomyelitis mice. J Neurophysiol. 2016;116(5):2173-2179. doi: 10.1152/jn.00510.2016
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Eurasian Journal of Medicine and Oncology, Electronic ISSN: 2587-196X Print ISSN: 2587-2400, Published by AccScience Publishing
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