Skip to main content

Advertisement

Log in

γ-Glutamylamines and neurodegenerative diseases

  • Invited Review
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

Transglutaminases catalyze the formation of γ-glutamylamines utilizing glutamyl residues and amine-bearing compounds such as lysyl residues and polyamines. These γ-glutamylamines can be released from proteins by proteases in an intact form. The free γ-glutamylamines can be catabolized to 5-oxo-L-proline and the free amine by γ-glutamylamine cyclotransferase. Free γ-glutamylamines, however, accumulate in the CSF and affected areas of Huntington Disease brain. This observation suggests transglutaminase-derived γ-glutamylamines may play a more significant role in neurodegeneration than previously thought. The following monograph reviews the metabolism of γ-glutamylamines and examines the possibility that these species contribute to neurodegeneration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Notes

  1. This is probably not the case for sporadic inclusion myositis. The increase in transglutaminase activity observed in this disease is accompanied by a remarkable accumulation of protein cross-linked with γ-glutamyl-ε-lysine linkages, in the periphery, which is thought to contribute significantly to the myositis (Choi et al. 2000).

References

  • Abe T, Chung SI, DiAugustine RP, Folk JE (1977) Rabbit liver transglutaminase: physical, chemical and catalytic properties. Biochemistry 16:5495–5501

    Article  PubMed  CAS  Google Scholar 

  • Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S (2004) Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431:805–810

    Article  PubMed  CAS  Google Scholar 

  • Beninati S, Martinet N, Folk JE (1988a) High-performance liquid chromatographic method for the determination of ε-(γ-glutamyl)lysine and mono- and bis-γ-glutamyl derivatives of putrescine and spermidine. J Chromatogr 443:329–335

    Article  PubMed  CAS  Google Scholar 

  • Beninati S, Piacentini M, Cocuzzi ET, Autuori F, Folk JE (1988b) Covalent incorporation of polyamines as γ-glutamyl derivatives into CHO cell protein. Biochim Biophys Acta 952:325–333

    Article  PubMed  CAS  Google Scholar 

  • Bisaglia M, Mammi S, Bubacco L (2007) Kinetic and structural analysis of the early oxidation products of dopamine: analysis of the interactions with α-synuclein. J Biol Chem 282:15597–15605

    Article  PubMed  CAS  Google Scholar 

  • Bisaglia M, Tosatto L, Munari F, Tessari I, de Laureto PP, Mammi S, Bubacco L (2010) Dopamine quinones interact with alpha-synuclein to form unstructured adducts. Biochem Biophys Res Commun 394:424–428

    Article  PubMed  CAS  Google Scholar 

  • Caccamo D, Curro M, Ientile R (2010) Potential of transglutaminase 2 as a therapeutic target. Expert Opin Ther Targets 14:989–1003

    Article  PubMed  CAS  Google Scholar 

  • Chen S-E (2008) Modeling, design, and development of potential inhibitors of γ-glutamylamine cyclotransferase and inhibitors of cruzain as therapeutic agents for Chagas’ disease Chemistry and Biochemistry Ph.D.

  • Choi YC, Park GT, Kim TS, Sunwoo IN, Steinert PM, Kim SY (2000) Sporadic inclusion body myositis correlates with increased expression and cross-linking by transglutaminases 1 and 2. J Biol Chem 275:8703–8710

    Article  PubMed  CAS  Google Scholar 

  • Chung SI, Folk JE (1972) Transglutaminase from hair follicle of guinea pig (crosslinking-fibrin-glutamyllysine-isoenzymes-purified enzyme). Proc Natl Acad Sci USA 69:303–307

    Article  PubMed  CAS  Google Scholar 

  • Citron BA, SantaCruz KS, Davies PJ, Festoff BW (2001) Intron–exon swapping of transglutaminase mRNA and neuronal Tau aggregation in Alzheimer’s disease. J Biol Chem 276:3295–3301

    Article  PubMed  CAS  Google Scholar 

  • Cooper AJL, Plum F (1987) Biochemistry and physiology of brain ammonia. Physiol Rev 67:440–519

    PubMed  CAS  Google Scholar 

  • Cooper AJL, Sheu KF, Burke JR, Onodera O, Strittmatter WJ, Roses AD, Blass JP (1997a) Polyglutamine domains are substrates of tissue transglutaminase: does transglutaminase play a role in expanded CAG/poly-Q neurodegenerative diseases? J Neurochem 69:431–434

    Article  PubMed  CAS  Google Scholar 

  • Cooper AJL, Sheu KR, Burke JR, Onodera O, Strittmatter WJ, Roses AD, Blass JP (1997b) Transglutaminase-catalyzed inactivation of glyceraldehyde 3-phosphate dehydrogenase and α-ketoglutarate dehydrogenase complex by polyglutamine domains of pathological length. Proc Natl Acad Sci USA 94:12604–12609

    Article  PubMed  CAS  Google Scholar 

  • Cooper AJL, Jeitner TM, Gentile V, Blass JP (2002) Cross linking of polyglutamine domains catalyzed by tissue transglutaminase is greatly favored with pathological-length repeats: does transglutaminase activity play a role in (CAG)n/Qn-expansion diseases? Neurochem Int 40:53–67

    Article  PubMed  CAS  Google Scholar 

  • Danson JW, Trawick ML, Cooper AJL (2002) Spectrophotometric assays for l-lysine α-oxidase and γ-glutamylamine cyclotransferase. Anal Biochem 303:120–130

    Article  PubMed  CAS  Google Scholar 

  • Dedeoglu A, Kubilus JK, Jeitner TM, Matson SA, Bogdanov M, Kowall NW, Matson WR, Cooper AJL, Ratan RR, Beal MF, Hersch SM, Ferrante RJ (2002) Therapeutic effects of cystamine in a murine model of Huntington’s disease. J Neurosci 22:8942–8950

    PubMed  CAS  Google Scholar 

  • Fasano M, Bergamasco B, Lopiano L (2006) Is neuromelanin changed in Parkinson’s disease? Investigations by magnetic spectroscopies. J Neural Transm 113:769–774

    Article  PubMed  CAS  Google Scholar 

  • Faucheux BA, Martin ME, Beaumont C, Hauw JJ, Agid Y, Hirsch EC (2003) Neuromelanin associated redox-active iron is increased in the substantia nigra of patients with Parkinson’s disease. J Neurochem 86:1142–1148

    Article  PubMed  CAS  Google Scholar 

  • Fedorow H, Halliday GM, Rickert CH, Gerlach M, Riederer P, Double KL (2006) Evidence for specific phases in the development of human neuromelanin. Neurobiol Aging 27:506–512

    Article  PubMed  CAS  Google Scholar 

  • Fésüs L, Szucs EF, Barrett KE, Metcalfe DD, Folk JE (1985) Activation of transglutaminase and production of protein-bound γ-glutamylhistamine in stimulated mouse mast cells. J Biol Chem 260:13771–13778

    PubMed  Google Scholar 

  • Fink ML, Folk JE (1981) γ-Glutamylamine cyclotransferase. An enzyme involved in the catabolism of ε-(γ-glutamyl)lysine and other γ-glutamylamines. Mol Cell Biochem 38(Spec No):59–67

    Google Scholar 

  • Fink ML, Folk JE (1983) γ-Glutamylamine cyclotransferase (rabbit kidney). Methods Enzymol 94:347–351

    Article  PubMed  CAS  Google Scholar 

  • Fink ML, Chung SI, Folk JE (1980) γ-Glutamylamine cyclotransferase: specificity toward epsilon-(L-gamma-glutamyl)-l-lysine and related compounds. Proc Natl Acad Sci USA 77:4564–4568

    Article  PubMed  CAS  Google Scholar 

  • Folk JE (1969) Mechanism of action of guinea pig liver transglutaminase, VI. Order of substrate addition. J Biol Chem 244:3707–3713

    PubMed  CAS  Google Scholar 

  • Folk JE (1983) Mechanism and basis for specificity of transglutaminase-catalyzed ε-(γ-glutamyl) lysine bond formation. Adv Enzymol Relat Areas Mol Biol 54:1–56

    PubMed  CAS  Google Scholar 

  • Folk JE, Cole PW (1966) Transglutaminase: mechanistic features of the active site as determined by kinetic and inhibitor studies. Biochim Biophys Acta 122:244–264

    Article  PubMed  CAS  Google Scholar 

  • Folk JE, Finlayson JS (1977) The ε-(γ-glutamyl)lysine crosslink and the catalytic role of transglutaminases. Adv Protein Chem 31:1–133

    Article  PubMed  CAS  Google Scholar 

  • Folk JE, Park MH, Chung SI, Schrode J, Lester EP, Cooper HL (1980) Polyamines as physiological substrates for transglutaminases. J Biol Chem 255:3695–3700

    PubMed  CAS  Google Scholar 

  • Gentile V, Sepe C, Calvani M, Melone MA, Cotrufo R, Cooper AJL, Blass JP, Peluso G (1998) 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 352:314–321

    Article  PubMed  CAS  Google Scholar 

  • Gibb WR (1992) Melanin, tyrosine hydroxylase calbindin and substance P in the human midbrain and substantia nigra in relation to nigrostriatal projections and differential neuronal susceptibility in Parkinson’s disease. Brain Res 581:283–291

    Article  PubMed  CAS  Google Scholar 

  • Good PF, Olanow CW, Perl DP (1992) Neuromelanin-containing neurons of the substantia nigra accumulate iron and aluminum in Parkinson’s disease: a LAMMA study. Brain Res 593:343–346

    Article  PubMed  CAS  Google Scholar 

  • Green H (1993) Human genetic diseases due to codon reiteration: relationship to an evolutionary mechanism. Cell 74:955–956

    Article  PubMed  CAS  Google Scholar 

  • Grenard P, Bates MK, Aeschlimann D (2001) Evolution of transglutaminase genes: identification of a transglutaminase gene cluster on human chromosome 15q15. Structure of the gene encoding transglutaminase X and a novel gene family member, transglutaminase. Z J Biol Chem 276:33066–33078

    Article  CAS  Google Scholar 

  • Gusella JF, MacDonald ME, Ambrose CM, Duyao MP (1993) Molecular genetics of Huntington’s disease. Arch Neurol 50:1157–1163

    Article  PubMed  CAS  Google Scholar 

  • Hadjivassiliou M, Aeschlimann P, Strigun A, Sanders DS, Woodroofe N, Aeschlimann D (2008) Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase. Ann Neurol 64:332–343

    Article  PubMed  CAS  Google Scholar 

  • Hartley DM, Zhao C, Speier AC, Woodard GA, Li S, Li Z, Walz T (2008) Transglutaminase induces protofibril-like amyloid beta-protein assemblies that are protease-resistant and inhibit long-term potentiation. J Biol Chem 283:16790–16800

    Article  PubMed  CAS  Google Scholar 

  • Hennings H, Steinert P, Buxman MM (1981) Calcium induction of transglutaminase and the formation of ε(γ-glutamyl) lysine cross-links in cultured mouse epidermal cells. Biochem Biophys Res Commun 102:739–745

    Article  PubMed  CAS  Google Scholar 

  • Herman ML, Farasat S, Steinbach PJ, Wei MH, Toure O, Fleckman P, Blake P, Bale SJ, Toro JR (2009) Transglutaminase-1 gene mutations in autosomal recessive congenital ichthyosis: summary of mutations (including 23 novel) and modeling of TGase-1. Hum Mutat 30:537–547

    Article  PubMed  CAS  Google Scholar 

  • Hoffner G, Hoppilliard Y, van der Rest G, Dansette P, Djian P, Ohanessian G (2008) [Nε-(γ-glutamyl) lysine] as a potential biomarker in neurological diseases: new detection method and fragmentation pathways. J Mass Spectrom 43:456–469

    Article  PubMed  CAS  Google Scholar 

  • Hoffner G, van der Rest G, Dansette PM, Djian P (2009) The end product of transglutaminase crosslinking: simultaneous quantitation of [Nε-(γ-glutamyl) lysine] and lysine by HPLC-MS3. Anal Biochem 384:296–304

    Article  PubMed  CAS  Google Scholar 

  • Hoffner G, Andre W, Vanhoutteghem A, Soues S, Djian P (2010) Transglutaminase-catalyzed crosslinking in neurological disease: from experimental evidence to therapeutic inhibition CNS. Neurol Disord Drug Targets 9:217–231

    CAS  Google Scholar 

  • Hoogeveen AT, Willemsen R, Meyer N, de Rooij KE, Roos RA, van Ommen GJ, Galjaard H (1993) Characterization and localization of the Huntington disease gene product. Hum Mol Genet 2:2069–2073

    Article  PubMed  CAS  Google Scholar 

  • Iismaa SE, Holman S, Wouters MA, Lorand L, Graham RM, Husain A (2003) Evolutionary specialization of a tryptophan indole group for transition-state stabilization by eukaryotic transglutaminases. Proc Natl Acad Sci USA 100:12636–12641

    Article  PubMed  CAS  Google Scholar 

  • Iismaa SE, Mearns BM, Lorand L, Graham RM (2009) Transglutaminases and disease: lessons from genetically engineered mouse models and inherited disorders. Physiol Rev 89:991–1023

    Article  PubMed  CAS  Google Scholar 

  • Jeitner TM, Bogdanov MB, Matson WR, Daikhin Y, Yudkoff M, Folk JE, Steinman L, Browne SE, Beal MF, Blass JP, Cooper AJL (2001) Nε-(γ-L-glutamyl)-l-lysine (GGEL) is increased in cerebrospinal fluid of patients with Huntington’s disease. J Neurochem 79:1109–1112

    Article  PubMed  CAS  Google Scholar 

  • Jeitner TM, Matson WR, Folk JE, Blass JP, Cooper AJL (2008) Increased levels of γ-glutamylamines in Huntington disease CSF. J Neurochem 106:37–44

    Article  PubMed  CAS  Google Scholar 

  • Jeitner TM, Muma NA, Battaile KP, Cooper AJL (2009a) Transglutaminase activation in neurodegenerative diseases. Future Neurol 4:449–467

    Article  PubMed  CAS  Google Scholar 

  • Jeitner TM, Pinto JT, Krasnikov BF, Horswill M, Cooper AJL (2009b) Transglutaminases and neurodegeneration. J Neurochem 109(Suppl 1):160–166

    Article  PubMed  CAS  Google Scholar 

  • Jellinger K, Kienzl E, Rumpelmair G, Riederer P, Stachelberger H, Ben-Shachar D, Youdim MB (1992) Iron-melanin complex in substantia nigra of parkinsonian brains: an X-ray microanalysis. J Neurochem 59:1168–1171

    Article  PubMed  CAS  Google Scholar 

  • Junn E, Ronchetti RD, Quezado MM, Kim SY, Mouradian MM (2003) Tissue transglutaminase-induced aggregation of α-synuclein: Implications for Lewy body formation in Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci USA 100:2047–2052

    Article  PubMed  CAS  Google Scholar 

  • Kahlem P, Green H, Djian P (1998) Transglutaminase action imitates Huntington’s disease: selective polymerization of Huntingtin containing expanded polyglutamine. Mol Cell 1:595–601

    Article  PubMed  CAS  Google Scholar 

  • Karpuj MV, Becher MW, Springer JE, Chabas D, Youssef S, Pedotti R, Mitchell D, Steinman L (2002) Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease with administration of the transglutaminase inhibitor cystamine. Nat Med 8:143–149

    Article  PubMed  CAS  Google Scholar 

  • Kastner A, Hirsch EC, Lejeune O, Javoy-Agid F, Rascol O, Agid Y (1992) Is the vulnerability of neurons in the substantia nigra of patients with Parkinson’s disease related to their neuromelanin content? J Neurochem 59:1080–1089

    Article  PubMed  CAS  Google Scholar 

  • Kim SY, Grant P, Lee JH, Pant HC, Steinert PM (1999) Differential expression of multiple transglutaminases in human brain. Increased expression and cross-linking by transglutaminases 1 and 2 in Alzheimer’s disease. J Biol Chem 274:30715–30721

    Article  PubMed  CAS  Google Scholar 

  • Kim SY, Jeitner TM, Steinert PM (2002) Transglutaminases in disease. Neurochem Int 40:85–103

    Article  PubMed  CAS  Google Scholar 

  • Konno T, Morii T, Shimizu H, Oiki S, Ikura K (2005) Paradoxical inhibition of protein aggregation and precipitation by transglutaminase-catalyzed intermolecular cross-linking. J Biol Chem 280:17520–17525

    Article  PubMed  CAS  Google Scholar 

  • Kuemmerle S, Gutekunst CA, Klein AM, Li XJ, Li SH, Beal MF, Hersch SM, Ferrante RJ (1999) Huntington aggregates may not predict neuronal death in Huntington’s disease. Ann Neurol 46:842–849

    Article  PubMed  CAS  Google Scholar 

  • Lai TS, Tucker T, Burke JR, Strittmatter WJ, Greenberg CS (2004) Effect of tissue transglutaminase on the solubility of proteins containing expanded polyglutamine repeats. J Neurochem 88:1253–1260

    Article  PubMed  CAS  Google Scholar 

  • Lesort M, Chun W, Johnson GV, Ferrante RJ (1999) Tissue transglutaminase is increased in Huntington’s disease brain. J Neurochem 73:2018–2027

    PubMed  CAS  Google Scholar 

  • Liu RM (2002) Down-regulation of γ-glutamylcysteine synthetase regulatory subunit gene expression in rat brain tissue during aging. J Neurosci Res 68:344–351

    Article  PubMed  CAS  Google Scholar 

  • Liu P, Gupta N, Jing Y, Zhang H (2008) Age-related changes in polyamines in memory-associated brain structures in rats. Neuroscience 155:789–796

    Article  PubMed  CAS  Google Scholar 

  • Lopiano L, Chiesa M, Digilio G, Giraudo S, Bergamasco B, Torre E, Fasano M (2000) Q-band EPR investigations of neuromelanin in control and Parkinson’s disease patients. Biochim Biophys Acta 1500:306–312

    Article  PubMed  CAS  Google Scholar 

  • Lorand L, Graham RM (2003) Transglutaminases: crosslinking enzymes with pleiotropic functions. Natl Rev Mol Cell Biol 4:140–156

    Article  CAS  Google Scholar 

  • Martinet N, Beninati S, Nigra TP, Folk JE (1990) N1N8-bis(γ-glutamyl)spermidine cross-linking in epidermal-cell envelopes. Comparison of cross-link levels in normal and psoriatic cell envelopes. Biochem J 271:305–308

    PubMed  CAS  Google Scholar 

  • Mastroberardino PG, Iannicola C, Nardacci R, Bernassola F, De Laurenzi V, Melino G, Moreno S, Pavone F, Oliverio S, Fésüs L, Piacentini M (2002) ‘Tissue’ transglutaminase ablation reduces neuronal death and prolongs survival in a mouse model of Huntington’s disease. Cell Death Differ 9:873–880

    Article  PubMed  CAS  Google Scholar 

  • McNicholas S, Potterton E, Wilson KS, Noble ME (2011) Presenting your structures: the CCP4 mg molecular-graphics software Acta Crystallogr D. Biol Crystallogr 67:386–394

    Article  CAS  Google Scholar 

  • Meister A (1985) γ-Glutamylcyclotransferase from rat kidney. Methods Enzymol 113:438–445

    Article  PubMed  CAS  Google Scholar 

  • Molberg O, McAdam SN, Korner R, Quarsten H, Kristiansen C, Madsen L, Fugger L, Scott H, Noren O, Roepstorff P, Lundin KE, Sjostrom H, Sollid LM (1998) Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med 4:713–717

    Article  PubMed  CAS  Google Scholar 

  • Nakajima T, Kakimoto Y, Tsuji M, Konishi H (1976) Occurrence and formation of γ-glutamylputrescine in mammalian brain. J Neurochem 26:115–118

    PubMed  CAS  Google Scholar 

  • Necula M, Kayed R, Milton S, Glabe CG (2007) Small molecule inhibitors of aggregation indicate that amyloid beta oligomerization and fibrillization pathways are independent and distinct. J Biol Chem 282:10311–10324

    Article  PubMed  CAS  Google Scholar 

  • Nemes Z, Marekov LN, Fésüs L, Steinert PM (1999) A novel function for transglutaminase 1: attachment of long-chain omega-hydroxyceramides to involucrin by ester bond formation. Proc Natl Acad Sci USA 96:8402–8407

    Article  PubMed  CAS  Google Scholar 

  • Nemes Z, Devreese B, Steinert PM, Van Beeumen J, Fésüs L (2004) Cross-linking of ubiquitin, HSP27, parkin and α-synuclein by γ-glutamyl-ε-lysine bonds in Alzheimer’s neurofibrillary tangles. FASEB J 18:1135–1137

    PubMed  CAS  Google Scholar 

  • Nemes Z, Petrovski G, Aerts M, Sergeant K, Devreese B, Fésüs L (2009) Transglutaminase-mediated intramolecular cross-linking of membrane-bound α-synuclein promotes amyloid formation in Lewy bodies. J Biol Chem 284:27252–27264

    Article  PubMed  CAS  Google Scholar 

  • Oakley AJ, Coggan M, Board PG (2010) Identification and characterization of γ-glutamylamine cyclotransferase, an enzyme responsible for γ-glutamyl-ε-lysine catabolism. J Biol Chem 285:9642–9648

    Article  PubMed  CAS  Google Scholar 

  • Ono K, Yamada M (2011) Low-n oligomers as therapeutic targets of Alzheimer’s disease. J Neurochem 117:19–28

    Article  PubMed  CAS  Google Scholar 

  • Parameswaran KN, Cheng XF, Chen EC, Velasco PT, Wilson JH, Lorand L (1997) Hydrolysis of γ:ε isopeptides by cytosolic transglutaminases and by coagulation factor XIIIa. J Biol Chem 272:10311–10317

    Article  PubMed  CAS  Google Scholar 

  • Perutz MF (1995) Glutamine repeats as polar zippers: their role in inherited neurodegenerative disease. Mol Med 1:718–721

    PubMed  CAS  Google Scholar 

  • Pham CL, Leong SL, Ali FE, Kenche VB, Hill AF, Gras SL, Barnham KJ, Cappai R (2009) Dopamine and the dopamine oxidation product 5, 6-dihydroxylindole promote distinct on-pathway and off-pathway aggregation of alpha-synuclein in a pH-dependent manner. J Mol Biol 387:771–785

    Article  PubMed  CAS  Google Scholar 

  • Piacentini M, Martinet N, Beninati S, Folk JE (1988) Free and protein-conjugated polyamines in mouse epidermal cells. Effect of high calcium and retinoic acid. J Biol Chem 263:3790–3794

    PubMed  CAS  Google Scholar 

  • Pinkas DM, Strop P, Brunger AT, Khosla C (2007) Transglutaminase 2 undergoes a large conformational change upon activation. PLoS Biol 5:e327

    Article  PubMed  CAS  Google Scholar 

  • Ricotta M, Iannuzzi M, Vivo GD, Gentile V (2010) Physio-pathological roles of transglutaminase-catalyzed reactions. World J Biol Chem 1:181–187

    Article  PubMed  Google Scholar 

  • Rubinsztein DC, Barton DE, Davison BC, Ferguson-Smith MA (1993) Analysis of the huntingtin gene reveals a trinucleotide-length polymorphism in the region of the gene that contains two CCG-rich stretches and a correlation between decreased age of onset of Huntington’s disease and CAG repeat number. Hum Mol Genet 2:1713–1715

    Article  PubMed  CAS  Google Scholar 

  • Ruoppolo M, Orru S, Francese S, Caputo I, Esposito C (2003) Structural characterization of transglutaminase-catalyzed cross-linking between glyceraldehyde 3-phosphate dehydrogenase and polyglutamine repeats. Protein Sci 12:170–179

    Article  PubMed  CAS  Google Scholar 

  • Saudou F, Finkbeiner S, Devys D, Greenberg ME (1998) Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95:55–66

    Article  PubMed  CAS  Google Scholar 

  • Schmid AW, Chiappe D, Pignat V, Grimminger V, Hang I, Moniatte M, Lashuel HA (2009) Dissecting the mechanisms of tissue transglutaminase-induced cross-linking of alpha-synuclein: implications for the pathogenesis of Parkinson disease. J Biol Chem 284:13128–13142

    Article  PubMed  CAS  Google Scholar 

  • Schmid AW, Condemi E, Tuchscherer G, Chiappe D, Mutter M, Vogel H, Moniatte M, Tsybin YO (2011) Tissue transglutaminase-mediated glutamine deamidation of beta-amyloid peptide increases peptide solubility, whereas enzymatic cross-linking and peptide fragmentation may serve as molecular triggers for rapid peptide aggregation. J Biol Chem 286:12172–12188

    Article  PubMed  CAS  Google Scholar 

  • Schmidt MH, Meyer GA, Reichert KW, Cheng J, Krouwer HG, Ozker K, Whelan HT (2004) Evaluation of photodynamic therapy near functional brain tissue in patients with recurrent brain tumors. J Neurooncol 67:201–207

    Article  PubMed  Google Scholar 

  • Segers-Nolten IM, Wilhelmus MM, Veldhuis G, van Rooijen BD, Drukarch B, Subramaniam V (2008) Tissue transglutaminase modulates α-synuclein oligomerization. Protein Sci 17:1395–1402

    Article  PubMed  CAS  Google Scholar 

  • Selkoe DJ, Abraham C, Ihara Y (1982) Brain transglutaminase: in vitro crosslinking of human neurofilament proteins into insoluble polymers. Proc Natl Acad Sci USA 79:6070–6074

    Article  PubMed  CAS  Google Scholar 

  • Serrano P, Pedrini B, Geralt M, Jaudzems K, Mohanty B, Horst R, Herrmann T, Elsliger MA, Wilson IA, Wuthrich K (2010) Comparison of NMR and crystal structures highlights conformational isomerism in protein active sites. Acta Crystallogr Sect F Struct Biol Cryst Commun 66:1393–1405

    Article  PubMed  CAS  Google Scholar 

  • Singer SM, Zainelli GM, Norlund MA, Lee JM, Muma NA (2002) Transglutaminase bonds in neurofibrillary tangles and paired helical filament tau early in Alzheimer’s disease. Neurochem Int 40:17–30

    Article  PubMed  CAS  Google Scholar 

  • Stamnaes J, Fleckenstein B, Sollid LM (2008) The propensity for deamidation and transamidation of peptides by transglutaminase 2 is dependent on substrate affinity and reaction conditions. Biochim Biophys Acta 1784:1804–1811

    Article  PubMed  CAS  Google Scholar 

  • Tate SS, Meister A (1985) γ-Glutamyl transpeptidase from kidney. Methods Enzymol 113:400–419

    Article  PubMed  CAS  Google Scholar 

  • van de Wal Y, Kooy Y, van Veelen P, Pena S, Mearin L, Papadopoulos G, Koning F (1998) Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J Immunol 161:1585–1588

    PubMed  Google Scholar 

  • Verhaar R, Jongenelen CA, Gerard M, Baekelandt V, Van Dam AM, Wilhelmus MM, Drukarch B (2011) Blockade of enzyme activity inhibits tissue transglutaminase-mediated transamidation of α-synuclein in a cellular model of Parkinson’s disease. Neurochem Int 58:785–793

    Google Scholar 

  • Wilhelmus MM, van Dam AM, Drukarch B (2008) Tissue transglutaminase: a novel pharmacological target in preventing toxic protein aggregation in neurodegenerative diseases. Eur J Pharmacol 585:464–472

    Article  PubMed  CAS  Google Scholar 

  • Wilhelmus MM, Grunberg SC, Bol JG, van Dam AM, Hoozemans JJ, Rozemuller AJ, Drukarch B (2009) Transglutaminases and transglutaminase-catalyzed cross-links colocalize with the pathological lesions in Alzheimer’s disease brain. Brain Pathol 19:612–622

    Article  PubMed  CAS  Google Scholar 

  • Wilhelmus MM, Verhaar R, Andringa G, Bol JG, Cras P, Shan L, Hoozemans JJ, Drukarch B (2011a) Presence of tissue transglutaminase in granular endoplasmic reticulum is characteristic of melanized neurons in Parkinson’s disease brain. Brain Pathol 21:130–139

    Article  PubMed  CAS  Google Scholar 

  • Wilhelmus MM, Verhaar R, Bol JG, van Dam AM, Hoozemans JJ, Rozemuller AJ, Drukarch B (2011b) Novel role of transglutaminase 1 in corpora amylacea formation? Neurobiol Aging 32:845–856

    Article  PubMed  CAS  Google Scholar 

  • Wilhelmus MM, de Jager M, Rozemuller AJ, Breve J, Bol JG, Eckert RL, Drukarch B (2012) Transglutaminase 1 and its regulator tazarotene-induced gene 3 localize to neuronal tau inclusions in tauopathies. J Pathol 226:132–142

    Article  PubMed  CAS  Google Scholar 

  • Zainelli GM, Ross CA, Troncoso JC, Muma NA (2003) Transglutaminase cross-links in intranuclear inclusions in Huntington disease. J Neuropathol Exp Neurol 62:14–24

    PubMed  CAS  Google Scholar 

  • Zainelli GM, Dudek NL, Ross CA, Kim SY, Muma NA (2005) Mutant huntingtin protein: a substrate for transglutaminase 1, 2, and 3. J Neuropathol Exp Neurol 64:58–65

    PubMed  CAS  Google Scholar 

  • Zecca L, Shima T, Stroppolo A, Goj C, Battiston GA, Gerbasi R, Sarna T, Swartz HM (1996) Interaction of neuromelanin and iron in substantia nigra and other areas of human brain. Neuroscience 73:407–415

    Article  PubMed  CAS  Google Scholar 

  • Zecca L, Fariello R, Riederer P, Sulzer D, Gatti A, Tampellini D (2002) The absolute concentration of nigral neuromelanin, assayed by a new sensitive method increases throughout the life and is dramatically decreased in Parkinson’s disease. FEBS Lett 510:216–220

    Article  PubMed  CAS  Google Scholar 

  • Zecca L, Bellei C, Costi P, Albertini A, Monzani E, Casella L, Gallorini M, Bergamaschi L, Moscatelli A, Turro NJ, Eisner M, Crippa PR, Ito S, Wakamatsu K, Bush WD, Ward WC, Simon JD, Zucca FA (2008) New melanic pigments in the human brain that accumulate in aging and block environmental toxic metals. Proc Natl Acad Sci USA 105:17567–17572

    Article  PubMed  CAS  Google Scholar 

  • Zemaitaitis MO, Lee JM, Troncoso JC, Muma NA (2000) Transglutaminase-induced cross-linking of tau proteins in progressive supranuclear palsy. J Neuropathol Exp Neurol 59:983–989

    PubMed  CAS  Google Scholar 

  • Zhang W, Johnson BR, Suri DE, Martinez J, Bjornsson TD (1998) Immunohistochemical demonstration of tissue transglutaminase in amyloid plaques. Acta Neuropathol 96:395–400

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to acknowledge the pertinent comments of Dr. J. Keillor with regard to the reversibility of the reactions catalyzed by transglutaminases. Support for the writing of this review came from the Theresa Santmann-Patnode award to TMJ and from Burke Program Project-2P01 AG14930 to AJLC. We are indebted to Jack Folk for his willingness to synthesize for us several of the γ-glutamylpolyamines mentioned in the text. Without his help our studies on the levels of γ-glutamylpolyamines in CSF would not have been possible. Jack was always courteous and helpful. With his passing, the field has lost a superb chemist and biochemist.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Thomas M. Jeitner.

Additional information

This review is dedicated to the memory of the late Dr. Jack Folk.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jeitner, T.M., Battaile, K. & Cooper, A.J.L. γ-Glutamylamines and neurodegenerative diseases. Amino Acids 44, 129–142 (2013). https://doi.org/10.1007/s00726-011-1209-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-011-1209-3

Keywords

Navigation