Transglutaminase inhibition: possible therapeutic mechanisms to protect cells from death in neurological disorders

Vittorio Gentile; Elenamaria Fioretti; Nicola Gaetano Gatta; Rosaria Romano

Abstract

Review Article

Transglutaminase inhibition: possible therapeutic mechanisms to protect cells from death in neurological disorders

Vittorio Gentile*, Elenamaria Fioretti, Nicola Gaetano Gatta and Rosaria Romano

Published: 25 July, 2017 | Volume 1 - Issue 1 | Pages: 026-038

Transglutaminases are a family of Ca2+-dependent enzymes which catalyze post-translational modifications of proteins. The main activity of these enzymes is the cross-linking of glutaminyl residues of a protein/peptide substrate to lysyl residues of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono-or bi-substituted/crosslinked adducts) or -OH groups (to form ester linkages). In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Transglutaminase activity has been suggested to be involved in molecular mechanisms responsible for both physiological and pathological processes. In particular, transglutaminase activity has been shown to be responsible for human autoimmune diseases, and Celiac Disease is just one of them. Interestingly, neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, supranuclear palsy, Huntington’s disease and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. Here we describe the possible molecular mechanisms by which these enzymes could be responsible for such diseases and the possible use of transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity.

Read Full Article HTML DOI: 10.29328/journal.hjbm.1001004 Cite this Article Read Full Article PDF

Keywords:
Transglutaminases; Post-translational Modifications of Proteins; Neurodegeneration; NF-kB; Neuroinflammation

References

Folk JE. Mechanism and basis for specificity of transglutaminase-catalyzed e-(g-glutamyl) lysine bond formation. Adv Enzymol Relat Areas Mol Biol. 1983; 54: 1-56. Ref.: https://goo.gl/MZtXQS
Lorand L, Conrad S M. Transglutaminases. Mol Cell Biochem. 1984; 58: 9-35. Ref.: https://goo.gl/uAd6qy
Piacentini M, Martinet N, Beninati S, Folk JE. Free and protein conjugated-polyamines in mouse epidermal cells. Effect of high calcium and retinoic acid. J Biol Chem. 1988; 263: 3790-3794. Ref.: https://goo.gl/47QA8F
Song Y, Kirkpatrick LL, Schilling AB, Helseth DL, Chabot N, et al. Transglutaminase and polyamination of tubulin: posttranslational modification for stabilizing axonal microtubules. Neuron. 2013; 78: 109-123. Ref.: https://goo.gl/8xamTn
Achyuthan KE, Greenberg CS. Identification of a guanosine triphosphate-binding site on guinea pig liver transglutaminase. Role of GTP and calcium ions in modulating activity. J Biol Chem. 1987; 262: 1901-1906. Ref.: https://goo.gl/GVXy9h
Hasegawa G, Suwa M, Ichikawa Y, Ohtsuka T, Kumagai S, et al. A novel function of tissue-type transglutaminase: protein disulfide isomerase. Biochem J. 2003; 373: 793-803. Ref.: https://goo.gl/J7PR9u
Lahav J, Karniel E, Bagoly Z, Sheptovitsky V, Dardik R, et al. Coagulation factor XIII serves as protein disulfide isomerase. Thromb Haemost. 2009; 101: 840-844. Ref.: https://goo.gl/sCnzMA
Iismaa SE, Mearns BM, Lorand L, Graham RM. Transglutaminases and disease: lessons from genetically engineered mouse models and inherited disorders. Physiol Rev. 2009; 89: 991-1023. Ref.: https://goo.gl/H9sRQC
Smethurst PA, Griffin M. Measurement of tissue transglutaminase activity in a permeabilized cell system: its regulation by calcium and nucleotides. Biochem J. 1996; 313: 803-808. Ref.: https://goo.gl/cVYj3d
Nakaoka H, Perez DM, Baek KJ, Das T, Husain A, et al. Gh: a GTP-binding protein with transglutaminase activity and receptor signalling function. Science 1994; 264: 1593-1596. Ref.: https://goo.gl/NdY8xz
Gentile V, Porta R, Chiosi E, Spina A, Valente F, et al. tTGase/G alpha h protein expression inhibits adenylate cyclase activity in Balb-C 3T3 fibroblasts membranes. Biochim Biophys Acta. 1997; 1357: 115-122. Ref.: https://goo.gl/zz6rVF
Nanda N, Iismaa SE, Owens WA, et al. Targeted inactivation of Gh/tissue transglutaminase II. J Biol Chem. 2001; 276: 20673-20678. Ref.: https://goo.gl/nvfyq4
Mian S, El Alaoui S, Lawry J, Gentile V, Davies PJ, et al. The importance of the GTP binding protein tissue transglutaminase in the regulation of cell cycle progression. FEBS Letters. 1995; 370: 27-31. Ref.: https://goo.gl/ddWehz
Olaisen B, Gedde-Dahl TJR, Teisberg P, Thorsby E, Siverts A, et al. A structural locus for coagulation factor XIIIA (F13A) is located distal to the HLA region on chromosome 6p in man. Am J Hum Genet. 1985; 37: 215-220. Ref.: https://goo.gl/NvA1Kn
Yamanishi K, Inazawa J, Liew FM, Nonomura K, Ariyama T, et al. Structure of the gene for human transglutaminase 1. J Biol Chem. 1992; 267: 17858-17863. Ref.: https://goo.gl/JMjQWB
Gentile V, Davies PJ, Baldini A. The human tissue transglutaminase gene maps on chromosome 20q12 by in situ fluorescence hybridization. Genomics. 1994; 20: 295-297. Ref.: https://goo.gl/oW3hdr
Wang M, Kim IG, Steinert PM, McBride OW. Assignment of the human transglutaminase 2 (TGM2) and transglutaminase 3 (TGM3) genes to chromosome 20q11.2. Genomics. 1994; 23: 721-722. Ref.: https://goo.gl/AArGWB
Gentile V, Grant F, Porta R.. Human prostate transglutaminase is localized on chromosome 3p21.33-p22 by in situ fluorescence hybridization. Genomics. 1995; 27: 219-220.
Grenard P, Bates MK, Aeschlimann D. Evolution of transglutaminase genes: identification of a transglutaminases gene cluster on human chromosome 15q. Structure of the gene encoding transglutaminase X and a novel gene family member, transglutaminase Z. J Biol Chem. 2001; 276: 33066-33078. Ref.: https://goo.gl/Hpkd7L
Thomas H, Beck K, Adamczyk M, Aeschlimann P, Langley M, et al. Transglutaminase 6: a protein associated with central nervous system development and motor function. Amino Acids. 2013; 44: 161-177. Ref.: https://goo.gl/ghKXLi
Bailey CD, Johnson GV. Developmental regulation of tissue transglutaminase in the mouse forebrain. J Neurochem. 2004; 91: 1369-1379. Ref.: https://goo.gl/vyNVAK
Kim SY, Grant P, Lee JH, Pant HC, Steinert PM. Differential expression of multiple transglutaminases in human brain. Increased expression and cross-linking by transglutaminase 1 and 2 in Alzheimer’s disease. J Biol Chem. 1999; 274: 30715-30721. Ref.: https://goo.gl/WYtcCc
lannaccone M, Giuberti G, De Vivo G, Caraglia M, Gentile V. Identification of a FXIIIA variant in human neuroblastoma cell lines. Int J Biochem Mol Biol. 2013; 4: 102-107. Ref.: https://goo.gl/jiPkov
Citron BA, Santa Cruz KS, Davies PJ, Festoff BW. Intron-exon swapping of transglutaminase mRNA and neuronal tau aggregation in Alzheimer’s disease. J Biol Chem. 2001; 276: 3295-3301. Ref.: https://goo.gl/kaoiR9
De Laurenzi V, Melino G. Gene disruption of tissue transglutaminase. Mol Cell Biol 2001; 21: 148–155. Ref.: https://goo.gl/EaYkTA
Mastroberardino PG, Iannicola C, Nardacci R, Bernassola F, De Laurenzi V, et al. ‘Tissue’ transglutaminase ablation reduces neuronal death and prolongs survival in a mouse model of Huntington’s disease. Cell Death Differ. 2002; 9: 873-880. Ref.: https://goo.gl/UFGgnZ
Lorand L, Graham RM. Transglutaminases: crosslinking enzymes with pleiotropic functions. Nature Mol Cell Biol. 2003; 4: 140-156. Ref.: https://goo.gl/uB25U4
Wolf J, Jäger C, Lachmann I, Schönknecht P, Morawski M, et al. Tissue transglutaminase is not a biochemical marker for Alzheimer’s disease. Neurobiol Aging. 2013; 34: 2495-2498. Ref.: https://goo.gl/k7fpBu
Wilhelmus MM, Drukarch B. Tissue transglutaminase is a biochemical marker for Alzheimer’s disease. Neurobiol Aging. 2014; 35: 3-4. Ref.: https://goo.gl/5HCQ3p
Wolf J, Jäger C, Morawski M, Lachmann I, Schönknecht P, et al. Tissue transglutaminase in Alzheimer’s disease-facts and fiction: a reply to “Tissue transglutaminase is a biochemical marker for Alzheimer’s disease”. Neurobiol Aging. 2014; 35: 5-9. Ref.: https://goo.gl/n6iGhe
Adams RD, Victor M. Principles of Neurology. McGraw-Hill, Inc. Ed. 1993.
Selkoe DJ, Salazar FJ, Ihara Y. Alzheimer’s disease: insolubility of partially purified paired helical filaments in sodium dodecyl sulfate and urea. Proc Natl Acad Sci USA. 1982; 215: 1243-1245. Ref.: https://goo.gl/6ttFbK
Grierson AJ, Johnson GV, Miller CC. Three different human isoforms and rat neurofilament light, middle and heavy chain proteins are cellular substrates for transglutaminase. Neurosci Lett. 2001; 298: 9-12. Ref.: https://goo.gl/n5qJcb
Singer SM, Zainelli GM, Norlund MA, Lee JM, Muma NA. Transglutaminase bonds in neurofibrillary tangles and paired helical filament t early in Alzheimer’s disease. Neurochem Int. 2002; 40: 17-30. Ref.: https://goo.gl/6sJKUe
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: 1226-1233. Ref.: https://goo.gl/XgxnaL
Jeitner TM, Matson WR, Folk JE, Blass JP, Cooper AJ. Increased levels of g-glutamylamines in Huntington disease CSF. J Neurochem. 2008; 106: 37-44. Ref.: https://goo.gl/uk1ek3
Dudek SM, Johnson GV. Transglutaminase facilitates the formation of polymers of the beta-amyloid peptide. Brain Res 1994; 651: 129-133. Ref.: https://goo.gl/fJ6Y6h
Hartley DM, Zhao C, Speier AC, Woodard GA, Li S, et al. Transglutaminase induces protofibril-like amyloid b protein assemblies that are protease-resistant and inhibit long-term potentiation. J Biol Chem. 2008; 283: 16790-16800. Ref.: https://goo.gl/3Ntz4n
Citron BA, Suo Z, SantaCruz K, Davies PJ, Qin F, et al. Protein crosslinking, tissue transglutaminase, alternative splicing and neurodegeneration. Neurochem Int. 2002; 40: 69-78. Ref.: https://goo.gl/5PLq8j
Junn E, Ronchetti RD, Quezado MM, Kim SY, Mouradian MM. Tissue transglutaminase-induced aggregation of a-synuclein: Implications for Lewy body formation in Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci USA. 2003; 100: 2047-2052. : https://goo.gl/Ch8MFv
Zemaitaitis MO, Lee JM, Troncoso JC, Muma NA. Transglutaminase-induced cross-linking of t proteins in progressive supranuclear palsy. J Neuropathol Exp Neurol. 2000; 59: 983-989. Ref. : https://goo.gl/Uy1D3R
Zemaitaitis MO, Kim SY, Halverson RA, Troncoso JC, Lee JM, et al. Transglutaminase activity, protein, and mRNA expression are increased in progressive supranuclear palsy. J Neuropathol Exp Neurol. 2003 ; 62: 173-184. Ref. : https://goo.gl/2fVehR
Iuchi S, Hoffner G, Verbeke P, Djian P, Green H. Oligomeric and polymeric aggregates formed by proteins containing expanded polyglutamine. Proc Natl Acad Sci USA. 2003; 100: 2409-2414. Ref.: https://goo.gl/iAgP4t
Gentile V, Sepe C, Calvani M, Melone MA, Cotrufo R, 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: 314-321. Ref.: https://goo.gl/PV65Tc
Kahlem P, Green H, Djian P. Transglutaminase action imitates Huntington’s disease: selective polymerization of huntingtin containing expanded polyglutamine. Mol Cell 1998; 1: 595-601. Ref.: https://goo.gl/WmmuSY
Karpuj MV, Garren H, Slunt H, Price DL, Gusella J, 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: 7388-7393. Ref.: https://goo.gl/VYQi2k
Segers-Nolten IM, Wilhelmus MM, Veldhuis G, Benjamin Drukarch, Benjamin Drukarch, subramaniam V, et al. Tissue transglutaminase modulates a-synuclein oligomerization. Protein Sci. 2008 ; 17: 1395–1402. Ref. : https://goo.gl/unCQRM
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: 1253-1260. Ref.: https://goo.gl/S1J74t
Konno T, Mori T, Shimizu H, et al.Paradoxical inhibition of protein aggregation and precipitation by transglutaminase-catalyzed intermolecular cross-linking. J Biol Chem. 2005; 280: 17520-17525. Ref.: https://goo.gl/Ry5GEK
The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosome. Cell. 1993; 72: 971-983. Ref.: https://goo.gl/qmv1AP
Banfi S, Chung MY, McCall AE, Chinault AC, Zoghbi HY, et al. Mapping and cloning of the critical region for the spinocerebellar ataxia type 1 gene (SCA1) in a yeast artificial chromosome contig spanning 1.2 Mb. Genomics. 1993; 18: 627-635. Ref.: https://goo.gl/ZvWKTJ
Sanpei K, Takano H, Igarashi S, Oyake M, Ishida Y, et al. Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet. 1996; 14: 277-284. Ref.: https://goo.gl/FzpaFG
Pujana MA, Volpini V, Estivill X. Large CAG/CTG repeat templates produced by PCR, usefulness for the DIRECT method of cloning genes with CAG/CTG repeat expansions. Nucleic Acids Res. 1998; 1: 1352-1353. Ref.: https://goo.gl/5GLDuz
Fletcher CF, Lutz CM, O’Sullivan TN, Shaughnessy JD Jr, Hawkes R, et al. Absence epilepsy in tottering mutant mice is associated with calcium channel defects. Cell. 1996; 87: 607-617. Ref.: https://goo.gl/7q7r2Y
Vincent JB, Neves-Pereira ML, Paterson AD, Yamamoto E, Parikh SV, et al. An unstable trinucleotide-repeat region on chromosome 13 implicated in spinocerebellar ataxia: a common expansion locus. Am J Hum Genet. 2000; 66: 819-829. : https://goo.gl/nBXuv9
Holmes SE, O’Hearn E, Margolis RL. Why is SCA12 different from other SCAs? Cytogenet Genome Res. 2003; 100: 189-197. Ref.: https://goo.gl/vZNHmg
Imbert G, Trottier Y, Beckmann J, Mandel JL.The gene for the TATA binding protein (TBP) that contains a highly polymorphic protein coding CAG repeat maps to 6q27. Genomics. 1994; 21: 667-668. : https://goo.gl/T7vNi1
La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991; 352: 77-79. : https://goo.gl/VLB1KC
Onodera O, Oyake M, Takano H, Ikeuchi T, Igarashi S, et al. Molecular cloning of a full-length cDNA for dentatorubral-pallidoluysian atrophy and regional expressions of the expanded alleles in the CNS. Am J Hum Genet. 1995; 57: 1050-1060. Ref.: https://goo.gl/AeuaVm
Cooper AJL, Sheu K-FR, Burke JR, Strittmatter WJ, Gentile V, et al. Pathogenesis of inclusion bodies in (CAG) n/Qn-expansion diseases with special reference to the role of tissue transglutaminase and to selective vulnerability. J Neurochem. 1999; 72: 889-899. Ref.: https://goo.gl/EqLyLf
Hadjivassiliou M, Maki M, Sanders DS, Williamson CA, Grünewald RA, et al.Autoantibody targeting of brain and intestinal transglutaminase in gluten ataxia. Neurology. 2006; 66: 373-377. Ref.: https://goo.gl/26qTHDc
Boscolo S, Lorenzon A, Sblattero D, Florian F, Stebel M, et al. Anti-transglutaminase antibodies cause ataxia in mice. Plos One. 2010; 5: 9698. Ref.: https://goo.gl/gnQJgY
Stamnaes J, Dorum S, Fleckenstein B, Aeschlimann D, Sollid LM. Gluten T cell epitope targeting by TG3 and TG6; implications for dermatitis herpetiformis and gluten ataxia. Amino Acids. 2010; 39: 1183-1191. Ref.: https://goo.gl/nMey3w
Lerner A, Matthias T. GUT-the Trojan horse in remote organs’ autoimmunity. J Clin Cell Immunol. 2016; 7: 401.
Matthias T, Jeremias P, Neidhofer S, Lerner A. The industrial food additive microbial transglutaminase, mimics the tissue transglutaminase and is immunogenic in celiac disease patients. Autoimmun Rev. 2016; 15: 1111-1119. Ref.: https://goo.gl/6BtgYn
Lerner A, Neidhofer S, Matthias T. Transglutaminase 2 and anti-transglutaminase 2 autoantibodies in celiac disease and beyond: Part A: TG2 double-edged sword: gut and extraintestinal involvement. Immunome Res. 2015; 11: 101-105.
Wakshlag JJ, Antonyak MA, Boehm JE, Boehm K, Cerione RA. Effects of tissue transglutaminase on beta-amyloid 1-42-induced apoptosis. Protein J 2006; 25: 83-94. Ref.: https://goo.gl/sbpHZh
Lee JH, Jeong J, Jeong EM, Cho SY, Kang JW, et al. Endoplasmic reticulum stress activates transglutaminase 2 leading to protein aggregation. Int J Mol Med. 2014; 33: 849-855. Ref.: https://goo.gl/RKBjLo
Grosso H, Woo JM, Lee KW, Im JY, Masliah E, et al. Transglutaminase 2 exacerbates α-synuclein toxicity in mice and yeast. FASEB J. 2014; 28: 4280-4291. Ref.: https://goo.gl/bQWkee
Zhang J, Wang S, Huang W, Bennett DA, Dickson DW, et al. Tissue transglutaminase and its product isopeptide are increased in Alzheimer’s disease and APPswe/PS1dE9 double transgenic mice brains. Mol Neurobiol. 2016; 53: 5066-5078. Ref.: https://goo.gl/FrtFxH
Wilhelmus MM, De JM, Smit AB, van der Loo RJ, Drukarch B. Catalytically active tissue transglutaminase colocalises with Ab pathology in Alzheimer’s disease mouse models. Sci Rep. 2016; 6: 20569. Ref.: https://goo.gl/9CXX9G
Wilhelmus MMM, De JM, Rozemuller AJM, Brevé J, Bol JG, et al.Transglutaminase 1 and its regulator Tazarotene-induced gene 3 localize to neuronal tau inclusions in tauopathies. J Pathol. 2012; 226: 132-142. Ref.: https://goo.gl/1bNwTs
Basso M, Berlin J, Xia L, Sleiman SF, Ko B, et al. Transglutaminase inhibition protects against oxidative stress-induced neuronal death downstream of pathological ERK activation. J Neurosci. 2012; 39: 6561-6569. Ref.: https://goo.gl/RgYNz5
Lee J, Kim YS, Choi DH, Bang MS, Han TR, et al.Transglutaminase 2 induces nuclear factor-kB activation via a novel pathway in BV-2 microglia. J Biol Chem. 2004; 279: 53725-53735. Ref.: https://goo.gl/4YD22W
Kumar S, Mehta K. Tissue transglutaminase constitutively activates HIF-1a promoter and nuclear factor-kB via a non-canonical pathway. Plos One. 2012; 7: 49321. Ref.: https://goo.gl/s4TNqZ
Lu S, Saydak M, Gentile V, Stein JP, Davies PJ. Isolation and characterization of the human tissue transglutaminase promoter. J Biol Chem. 1995; 270: 9748-9755. Ref.: https://goo.gl/Zd4Psg
Ientile R, Currò M, Caccamo D. Transglutaminase 2 and neuroinflammation. Amino Acids. 2015; 47: 19-26. Ref.: https://goo.gl/pVvQY8
Griffith OW, Larsson A, Meister A. Inhibition of g-glutamylcysteine synthetase by cystamine: an approach to a therapy of 5-oxoprolinuria (pyroglutamic aciduria). Biochem Biophys Res Commun. 1977; 79: 919-925. Ref.: https://goo.gl/Jh9aYN
Igarashi S, Koide R, Shimohata T, Yamada M, Hayashi Y, et al. Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch. Nat Genet. 1998; 18: 111-117. Ref.: https://goo.gl/jUNMtb
Karpuj MV, Becher MW, Springer JE, Chabas D, Youssef S, et al.Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine. Nat Med. 2002; 8: 143-149. Ref.: https://goo.gl/rndteF
Dedeoglu A, Kubilus JK, Jeitner TM, Matson SA, Bogdanov M, et al. Therapeutic effects of cystamine in a murine model of Huntington’s disease. J Neurosci. 2002; 22: 8942-8950. Ref.: https://goo.gl/HFN37j
Lesort M, Lee M, Tucholski J, Johnson GV. Cystamine inhibits caspase activity. Implications for the treatment of polyglutamine disorders. J Biol Chem. 2003; 278: 3825-3830. Ref.: https://goo.gl/WvVYVR
Dubinsky R, Gray C. CYTE-I-HD: Phase I dose finding and tolerability study of Cysteamine (Cystagon) in Huntington’s disease. Movement Disord. 2006; 21: 530-533. Ref.: https://goo.gl/8tVNpk
Langman CB, Greenbaum LA, Sarwal M, Grimm P, Niaudet P, et al. A randomized controlled crossover trial with delayed-release cysteamine bitartrate in nephropathic cystinosis: effectiveness on white blood cell cystine levels and comparison of safety. Clin J Am Soc Nephrol. 2012; 7: 1112-1120. : https://goo.gl/cdgC1S
Besouw M, Masereeuw R, Van DHL, Levtchenko E. Cysteamine: an old drug with new potential. Drug Discov Today. 2013; 18: 785-792. Ref.: https://goo.gl/57XnyQ
Hadjivassiliou M, Aeschlimann P, Strigun A, Sanders DS, Woodroofe N, et al. Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase. Ann Neurol. 2008; 64: 332-343. Ref.: https://goo.gl/6nc1rD
Krasnikov BF, Kim SY, McConoughey SJ, Ryu H, Xu H, et al. Transglutaminase activity is present in highly purified nonsynaptosomal mouse brain and liver mitochondria. Biochemistry. 2005; 44: 7830-7843. : https://goo.gl/ZoXaCr
Liliana B. Menalled, Kudwa AE, Oakeshott S, Andrew Farrar, Neil Paterson, et al. Genetic deletion of transglutaminase 2 does not rescue the phenotypic deficits observed in R6/2 and zQ175 mouse models of Huntington’s disease. Plos One. 2014; 9: 99520. Ref.: https://goo.gl/pF1NcS
Bailey CD, Johnson GV. Tissue transglutaminase contributes to disease progression in the R6/2 Huntington’s disease mouse model via aggregate-independent mechanisms. J Neurochem. 2005; 92: 83-92. Ref.: https://goo.gl/iX3VfA
Davies JE, Rose C, Sarkar S, Rubinsztein DC.Cystamine suppresses polyalanine toxicity in a mouse model of oculopharyngeal muscular dystrophy. Sci Transl Med. 2010; 2: 34-40. : https://goo.gl/HcNjQ3
Pietsch M, Wodtke R, Pietzsch J, Löser R. Tissue transglutaminase: An emerging target for therapy and imaging. Bioorg Med Chem Lett. 2013; 23: 6528-6543. Ref.: https://goo.gl/Shgc3j
Bhatt MP, Lim YC, Hwang J, Na S, Kim YM, et al. C-peptide prevents hyperglycemia-induced endothelial apoptosis through inhibition of reactive oxygen species-mediated transglutaminase 2 activation. Diabetes. 2013; 62: 243-253. Ref.: https://goo.gl/U1EbFJ

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University of Port Harcourt Teaching Hospital, Nigeria

Dr. Elizabeth A Awoyesuku

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Ekiti State University, Nigeria

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Diaverum: PADC, Jeddah, Saudi Arabia

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BS, PharmD., MBA, CPHIMS, FHIMSS, Adjunct Professor, Global Healthcare Management, MCPHS University, Chief Strategy Offi cer, MedicaSoft, Senior Advisor, National Health IT (NHIT) Collaborative for Underserved, New York HIMSS, National Liaison, Health 2.0 Boston, Past Chair, Chair Innovation, USA

Helen Figge

Ph.D, Boston University Department of Communication Sciences and Disorders and Knowledge Research Institute, Inc., 2131 Reflection Bay Drive, Arlington, Texas 76013, USA