Skip to main content
SpringerLink
Log in
Book cover

Protein Deimination in Human Health and Disease pp 237–255Cite as

Deimination in Alzheimer’s Disease

  • Chapter
  • First Online:

Abstract

Peptidylarginine deiminases (PADs) are a group of posttranslational modification enzymes that citrullinate (deiminate) protein arginine residues in a calcium ion-dependent manner. Enzymatic citrullination abolishes positive charges of native protein molecules, inevitably causing significant alterations in their structure and functions. Deiminated protein provides the important physiological advantage of forming a cornified layer of skin that covers the human body (see Chap. 7 for more details). Despite this beneficial function, deimination also has a negative side, because the accumulation of these proteins in the brain is a possible cause of Alzheimer’s disease (AD). In this chapter, we introduce PADs and their protein citrullination function, which is now considered critical for advancing research on aging and neurodegenerative disorders, especially AD.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   159.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Abbreviations

anti-CCP:

Anti-cyclic citrullinated peptide

anti-MVC:

Anti-mutated citrullinated vimentin,

AD:

Alzheimer’s disease

BAEE:

Benzoyl-l-arginine ethyl ester

Bz-l-Arg:

Benzoyl-l-arginine

Calbindin:

Calbindin-D-28K

CNS:

Central nervous system

DAB:

3,3′-Diaminobenzidine

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GFAP:

Glial fibrillary acidic protein

NFT:

Neurofibrillary tangles

MAP2:

Microtubule-associated protein 2

MBP:

Myelin basic protein

Nef3:

Neurofilament 3

PAD:

Peptidylarginine deiminase

RA:

Rheumatoid arthritis

RT-PCR:

Reverse transcriptase-polymerase chain reaction

SP:

Senile plaque

References

  • Akiyama K, Sakurai Y, Asou H, Senshu T (1999) Localization of peptidylarginine deiminase type II in a stage-specific immature oligodendrocyte from rat cerebral hemisphere. Neurosci Lett 274:53–55

    Article  PubMed  CAS  Google Scholar 

  • Asaga H, Ishigami A (2000) Protein deimination in the rat brain: generation of citrulline-containing proteins in cerebrum perfused with oxygen-deprived media. Biomed Res 21:197–205

    CAS  Google Scholar 

  • Asaga H, Ishigami A (2001) Protein deimination in the rat brain after kainate administration: citrulline-containing proteins as a novel marker of neurodegeneration. Neurosci Lett 299:5–8

    Article  PubMed  CAS  Google Scholar 

  • Asaga H, Senshu T (1993) Combined biochemical and immunocytochemical analyses of postmortem protein deimination in the rat spinal cord. Cell Biol Int 17:525–532

    Article  PubMed  CAS  Google Scholar 

  • Asaga H, Yamada M, Senshu T (1998) Selective deimination of vimentin in calcium ionophore-induced apoptosis of mouse peritoneal macrophages. Biochem Biophys Res Commun 243:641–646

    Article  PubMed  CAS  Google Scholar 

  • Asaga H, Nakashima K, Senshu T, Ishigami A, Yamada M (2001) Immunocytochemical localization of peptidylarginine deiminase in human eosinophils and neutrophils. J Leukoc Biol 70:46–51

    PubMed  CAS  Google Scholar 

  • Asaga H, Akiyama K, Ohsawa T, Ishigami A (2002) Increased and type II-specific expression of peptidylarginine deiminase in activated microglia but not hyperplastic astrocytes following kainic acid-evoked neurodegeneration in the rat brain. Neurosci Lett 326:129–132

    Article  PubMed  CAS  Google Scholar 

  • Bartzokis G (2004) Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer’s disease. Neurobiol Aging 25:5–18, author reply 49-62

    Article  PubMed  CAS  Google Scholar 

  • Boyde TR, Rahmatullah M (1980) Optimization of conditions for the colorimetric determination of citrulline, using diacetyl monoxime. Anal Biochem 107:424–431

    Article  PubMed  CAS  Google Scholar 

  • Chavanas S, Mechin MC, Takahara H et al (2004) Comparative analysis of the mouse and human peptidylarginine deiminase gene clusters reveals highly conserved non-coding segments and a new human gene, PADI6. Gene 330:19–27

    Article  PubMed  CAS  Google Scholar 

  • Cheron G, Servais L, Dan B (2008) Cerebellar network plasticity: from genes to fast oscillation. Neuroscience 153:1–19

    Article  PubMed  CAS  Google Scholar 

  • Choi DW (1988) Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. Trends Neurosci 11:465–469

    Article  PubMed  CAS  Google Scholar 

  • Erickson MA, Haburcak M, Smukler L, Dunlap K (2007) Altered functional expression of Purkinje cell calcium channels precedes motor dysfunction in tottering mice. Neuroscience 150:547–555

    Article  PubMed  CAS  Google Scholar 

  • Gould RM, Freund CM, Palmer F, Feinstein DL (2000) Messenger RNAs located in myelin sheath assembly sites. J Neurochem 75:1834–1844

    Article  PubMed  CAS  Google Scholar 

  • Guerrin M, Ishigami A, Mechin MC et al (2003) cDNA cloning, gene organization and expression analysis of human peptidylarginine deiminase type I. Biochem J 370:167–174

    Article  PubMed  CAS  Google Scholar 

  • Halvorsen EH, Pollmann S, Gilboe IM et al (2008) Serum IgG antibodies to peptidylarginine deiminase 4 in rheumatoid arthritis and associations with disease severity. Ann Rheum Dis 67:414–417

    Article  PubMed  CAS  Google Scholar 

  • Haun SE, Murphy EJ, Bates CM, Horrocks LA (1992) Extracellular calcium is a mediator of astroglial injury during combined glucose-oxygen deprivation. Brain Res 593:45–50

    Article  PubMed  CAS  Google Scholar 

  • Hossmann KA (1999) The hypoxic brain. insights from ischemia research. Adv Exp Med Biol 474:155–169

    PubMed  CAS  Google Scholar 

  • Imparl JM, Senshu T, Graves DJ (1995) Studies of calcineurin-calmodulin interaction: probing the role of arginine residues using peptidylarginine deiminase. Arch Biochem Biophys 318:370–377

    Article  PubMed  CAS  Google Scholar 

  • Inagaki M, Takahara H, Nishi Y, Sugawara K, Sato C (1989) Ca2+-dependent deimination-induced disassembly of intermediate filaments involves specific modification of the amino-terminal head domain. J Biol Chem 264:18119–18127

    PubMed  CAS  Google Scholar 

  • Ishigami A, Ohsawa T, Watanabe K, Senshu T (1996) All-trans retinoic acid increases peptidylarginine deiminases in a newborn rat keratinocyte cell line. Biochem Biophys Res Commun 223:299–303

    Article  PubMed  CAS  Google Scholar 

  • Ishigami A, Kuramoto M, Yamada M, Watanabe K, Senshu T (1998) Molecular cloning of two novel types of peptidylarginine deiminase cDNAs from retinoic acid-treated culture of a newborn rat keratinocyte cell line. FEBS Lett 433:113–118

    Article  PubMed  CAS  Google Scholar 

  • Ishigami A, Asaga H, Ohsawa T, Akiyama K, Maruyama N (2001) Peptidylarginine deiminase type I, type II, type III and type IV are expressed in rat epidermis. Biomed Res 22:63–65

    CAS  Google Scholar 

  • Ishigami A, Ohsawa T, Asaga H, Akiyama K, Kuramoto M, Maruyama N (2002) Human peptidylarginine deiminase type II: molecular cloning, gene organization, and expression in human skin. Arch Biochem Biophys 407:25–31

    Article  PubMed  CAS  Google Scholar 

  • Ishigami A, Ohsawa T, Hiratsuka M et al (2005) Abnormal accumulation of citrullinated proteins catalyzed by peptidylarginine deiminase in hippocampal extracts from patients with Alzheimer’s disease. J Neurosci Res 80:120–128

    Article  PubMed  CAS  Google Scholar 

  • Jang B, Kim E, Choi JK et al (2008) Accumulation of citrullinated proteins by up-regulated peptidylarginine deiminase 2 in brains of scrapie-infected mice: a possible role in pathogenesis. Am J Pathol 173:1129–1142

    Article  PubMed  CAS  Google Scholar 

  • Jang B, Jin JK, Jeon YC et al (2010) Involvement of peptidylarginine deiminase-mediated post-translational citrullination in pathogenesis of sporadic Creutzfeldt-Jakob disease. Acta Neuropathol 119:199–210

    Article  PubMed  CAS  Google Scholar 

  • Jang B, Shin HY, Choi JK et al (2011) Subcellular localization of peptidylarginine deiminase 2 and citrullinated proteins in brains of scrapie-infected mice: nuclear localization of PAD2 and membrane fraction-enriched citrullinated proteins. J Neuropathol Exp Neurol 70:116–124

    Article  PubMed  CAS  Google Scholar 

  • Jang B, Jeon YC, Choi JK et al (2012) Peptidylarginine deiminase modulates the physiological roles of enolase via citrullination: links between altered multifunction of enolase and neurodegenerative diseases. Biochem J 445:183–192

    PubMed  CAS  Google Scholar 

  • Kanno T, Kawada A, Yamanouchi J et al (2000) Human peptidylarginine deiminase type III: molecular cloning and nucleotide sequence of the cDNA, properties of the recombinant enzyme, and immunohistochemical localization in human skin. J Invest Dermatol 115:813–823

    Article  PubMed  CAS  Google Scholar 

  • Katzman R (1986) Alzheimer’s disease. N Engl J Med 314:964–973

    Article  PubMed  CAS  Google Scholar 

  • Keilhoff G, Prell T, Langnaese K et al (2008) Expression pattern of peptidylarginine deiminase in rat and human Schwann cells. Dev Neurobiol 68:101–114

    Article  PubMed  CAS  Google Scholar 

  • Keller JN, Hanni KB, Markesbery WR (2000) Impaired proteasome function in Alzheimer’s disease. J Neurochem 75:436–439

    Article  PubMed  CAS  Google Scholar 

  • Kubilus J, Baden HP (1983) Purification and properties of a brain enzyme which deiminates proteins. Biochim Biophys Acta 745:285–291

    Article  PubMed  CAS  Google Scholar 

  • Kubilus J, Waitkus RF, Baden HP (1980) Partial purification and specificity of an arginine-converting enzyme from bovine epidermis. Biochim Biophys Acta 615:246–251

    Article  PubMed  CAS  Google Scholar 

  • Lamensa JW, Moscarello MA (1993) Deimination of human myelin basic protein by a peptidylarginine deiminase from bovine brain. J Neurochem 61:987–996

    Article  PubMed  CAS  Google Scholar 

  • Liu YL, Chiang YH, Liu GY, Hung HC (2011) Functional role of dimerization of human peptidylarginine deiminase 4 (PAD4). PLoS One 6:e21314

    Article  PubMed  CAS  Google Scholar 

  • Maccioni RB, Munoz JP, Barbeito L (2001) The molecular bases of Alzheimer’s disease and other neurodegenerative disorders. Arch Med Res 32:367–381

    Article  PubMed  CAS  Google Scholar 

  • Mastronardi FG, Wood DD et al (2006) Increased citrullination of histone H3 in multiple sclerosis brain and animal models of demyelination: a role for tumor necrosis factor-induced peptidylarginine deiminase 4 translocation. J Neurosci 26:11387–11396

    Article  PubMed  CAS  Google Scholar 

  • Matsushita K, Wakamori M, Rhyu IJ et al (2002) Bidirectional alterations in cerebellar synaptic transmission of tottering and rolling Ca2+ channel mutant mice. J Neurosci 22:4388–4398

    PubMed  CAS  Google Scholar 

  • Moscarello MA, Wood DD, Ackerley C, Boulias C (1994) Myelin in multiple sclerosis is developmentally immature. J Clin Invest 94:146–154

    Article  PubMed  CAS  Google Scholar 

  • Moscarello MA, Pritzker L, Mastronardi FG, Wood DD (2002) Peptidylarginine deiminase: a candidate factor in demyelinating disease. J Neurochem 81:335–343

    Article  PubMed  CAS  Google Scholar 

  • Moscarello MA, Mastronardi FG, Wood DD (2007) The role of citrullinated proteins suggests a novel mechanism in the pathogenesis of multiple sclerosis. Neurochem Res 32:251–256

    Article  PubMed  CAS  Google Scholar 

  • Musse AA, Li Z, Ackerley CA et al (2008) Peptidylarginine deiminase 2 (PAD2) overexpression in transgenic mice leads to myelin loss in the central nervous system. Dis Model Mech 1:229–240

    Article  PubMed  CAS  Google Scholar 

  • Nakashima K, Hagiwara T, Ishigami A et al (1999) Molecular characterization of peptidylarginine deiminase in HL-60 cells induced by retinoic acid and 1α,25-dihydroxyvitamin D3. J Biol Chem 274:27786–27792

    Article  PubMed  CAS  Google Scholar 

  • Nicholas AP (2011) Dual immunofluorescence study of citrullinated proteins in Parkinson diseased substantia nigra. Neurosci Lett 495:26–29

    Article  PubMed  CAS  Google Scholar 

  • Nishijyo T, Kawada A, Kanno T, Shiraiwa M, Takahara H (1997) Isolation and molecular cloning of epidermal- and hair follicle-specific peptidylarginine deiminase (type III) from rat. J Biochem 121:868–875

    Article  PubMed  CAS  Google Scholar 

  • Rogers GE, Simmonds DH (1958) Content of citrulline and other amino acids in a protein of hair follicles. Nature 182:186–187

    Article  PubMed  CAS  Google Scholar 

  • Rus’d AA, Ikejiri Y, Ono H et al (1999) Molecular cloning of cDNAs of mouse peptidylarginine deiminase type I, type III and type IV, and the expression pattern of type I in mouse. Eur J Biochem 259:660–669

    Article  PubMed  Google Scholar 

  • Senshu T, Sato T, Inoue T, Akiyama K, Asaga H (1992) Detection of citrulline residues in deiminated proteins on polyvinylidene difluoride membrane. Anal Biochem 203:94–100

    Article  PubMed  CAS  Google Scholar 

  • Senshu T, Akiyama K, Kan S, Asaga H, Ishigami A, Manabe M (1995) Detection of deiminated proteins in rat skin: probing with a monospecific antibody after modification of citrulline residues. J Invest Dermatol 105:163–169

    Article  PubMed  CAS  Google Scholar 

  • Senshu T, Akiyama K, Ishigami A, Nomura K (1999) Studies on specificity of peptidylarginine deiminase reactions using an immunochemical probe that recognizes an enzymatically deiminated partial sequence of mouse keratin K1. J Dermatol Sci 21:113–126

    Article  PubMed  CAS  Google Scholar 

  • Serdaroglu M, Cakirbay H, Deger O, Cengiz S, Kul S (2008) The association of anti-CCP antibodies with disease activity in rheumatoid arthritis. Rheumatol Int 28:965–970

    Article  PubMed  Google Scholar 

  • Servais L, Bearzatto B, Schwaller B et al (2005) Mono- and dual-frequency fast cerebellar oscillation in mice lacking parvalbumin and/or calbindin D-28k. Eur J Neurosci 22:861–870

    Article  PubMed  CAS  Google Scholar 

  • Shimada N, Handa S, Uchida Y et al (2010) Developmental and age-related changes of peptidylarginine deiminase 2 in the mouse brain. J Neurosci Res 88:798–806

    PubMed  CAS  Google Scholar 

  • Smith MA (1998) Alzheimer disease. Int Rev Neurobiol 42:1–54

    PubMed  CAS  Google Scholar 

  • Suzuki A, Yamada R, Chang X et al (2003) Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 34:395–402

    Article  PubMed  CAS  Google Scholar 

  • Takizawa Y, Sawada T, Suzuki A, Yamada R, Inoue T, Yamamoto K (2005) Peptidylarginine deiminase 4 (PADI4) identified as a conformation-dependent autoantigen in rheumatoid arthritis. Scand J Rheumatol 34:212–215

    Article  PubMed  CAS  Google Scholar 

  • Tarcsa E, Marekov LN, Mei G, Melino G, Lee S-C, Steinert PM (1996) Protein unfolding by peptidylarginine deiminase. substrate specificity and structural relationships of the natural substrates trichohyalin and filaggrin. J Biol Chem 271:30709–30716

    Article  PubMed  CAS  Google Scholar 

  • Terakawa H, Takahara H, Sugawara K (1991) Three types of mouse peptidylarginine deiminase: characterization and tissue distribution. J Biochem 110:661–666

    PubMed  CAS  Google Scholar 

  • Tian J, Shi J, Bailey K, Mann DM (2004) Relationships between arteriosclerosis, cerebral amyloid angiopathy and myelin loss from cerebral cortical white matter in Alzheimer’s disease. Neuropathol Appl Neurobiol 30:46–56

    Article  PubMed  CAS  Google Scholar 

  • Tsuchida M, Takahara H, Minami N et al (1993) cDNA nucleotide sequence and primary structure of mouse uterine peptidylarginine deiminase. Detection of a 3′-untranslated nucleotide sequence common to the mRNA of transiently expressed genes and rapid turnover of this enzyme’s mRNA in the estrous cycle. Eur J Biochem 215:677–685

    Article  PubMed  CAS  Google Scholar 

  • Vincent SR, Leung E, Watanabe K (1992) Immunohistochemical localization of peptidylarginine deiminase in the rat brain. J Chem Neuroanat 5:159–168

    Article  PubMed  CAS  Google Scholar 

  • Wagner E, Skoumal M, Bayer PM, Klaushofer K (2009) Antibody against mutated citrullinated vimentin: a new sensitive marker in the diagnosis of rheumatoid arthritis. Rheumatol Int 29:1315–1321

    Article  PubMed  CAS  Google Scholar 

  • Watanabe K, Senshu T (1989) Isolation and characterization of cDNA clones encoding rat skeletal muscle peptidylarginine deiminase. J Biol Chem 264:15255–15260

    PubMed  CAS  Google Scholar 

  • Watanabe K, Akiyama K, Hikichi K, Ohtsuka R, Okuyama A, Senshu T (1988) Combined biochemical and immunochemical comparison of peptidylarginine deiminases present in various tissues. Biochim Biophys Acta 966:375–383

    Article  PubMed  CAS  Google Scholar 

  • Whitney ER, Kemper TL, Bauman ML, Rosene DL, Blatt GJ (2008) Cerebellar Purkinje cells are reduced in a subpopulation of autistic brains: a stereological experiment using calbindin-D28k. Cerebellum 7:406–416

    Article  PubMed  CAS  Google Scholar 

  • Wood DD, Ackerley CA, Brand B et al (2008) Myelin localization of peptidylarginine deiminases 2 and 4: comparison of PAD2 and PAD4 activities. Lab Invest 88:354–364

    Article  PubMed  CAS  Google Scholar 

  • Zarabian B, Koushesh F, Vassef A (1987) Modified methods for measuring citrulline and carbamoyl-β-alanine with reduced light sensitivity and sucrose interference. Anal Biochem 166:113–119

    Article  PubMed  CAS  Google Scholar 

  • Zhao J, Zhao Y, He J, Jia R, Li Z (2008) Prevalence and significance of anti-peptidylarginine deiminase 4 antibodies in rheumatoid arthritis. J Rheumatol 35:969–974

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The excellent editorial assistance of Ms. P. Minick is gratefully acknowledged.

Author information

Authors and Affiliations

  1. Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan

    Akihito Ishigami Ph.D. & Naoki Maruyama

  2. Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology (TMIG), 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan

    Akihito Ishigami Ph.D.

  3. Ilsong Institute of Life Science, Hallym University, Anyang, 431-060, Republic of Korea

    Eun-Kyoung Choi & Yong-Sun Kim

Authors
  1. Akihito Ishigami Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eun-Kyoung Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yong-Sun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Naoki Maruyama
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Akihito Ishigami Ph.D. .

Editor information

Editors and Affiliations

  1. Department of Neurology, University of Alabama at Birmingham and The Birmingham Veterans Administration Medical Center, Birmingham, Alabama, USA

    Anthony P. Nicholas

  2. Bascom Palmer Eye Institute, University of Miami, MIAMI, Florida, USA

    Sanjoy K. Bhattacharya

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Ishigami, A., Choi, EK., Kim, YS., Maruyama, N. (2014). Deimination in Alzheimer’s Disease. In: Nicholas, A., Bhattacharya, S. (eds) Protein Deimination in Human Health and Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8317-5_13

Download citation

Publish with us

Policies and ethics

Search

Navigation