Citrullination of central nervous system proteins during the development of experimental autoimmune encephalomyelitis

Raijmakers, Reinout; Vogelzangs, Judith; Croxford, J. Ludovic; Wesseling, Pieter; Venrooij, Walther J. van; Pruijn, Ger J. M.

doi:10.1002/cne.20529

Cited by 45 publications

(55 citation statements)

References 32 publications

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“…Normal white matter samples from brains of MS patients and white matter from non-neurological controls were obtained from the MS tissue bank at UCLA. Human recombinant PAD2 and PAD4 (EC 3.5-3.15) were prepared as described by Raijmakers et al 18 and supplied to us for this study. The normal mice used for this study were on the CD-1 background, and were housed in the Hospital for Sick Children Animal Care facility.…”

Section: Methodsmentioning

confidence: 99%

“…22 The isotype-specific anti-PAD2 antibody was generated by immunization with two peptides comprising amino acids 3-18 and 516-531 of human PAD2. 18,19 The PAD4 isotype-specific antibody was raised against peptides 180-194 of human PAD4. 18 The monoclonal anticitrulline antibody, MAbF95 23 was obtained from Dr A Nicholas, Birmingham, Alabama.…”

Section: Preparation Of Myelinmentioning

confidence: 99%

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Myelin localization of peptidylarginine deiminases 2 and 4: comparison of PAD2 and PAD4 activities

Wood

Ackerley

Brand

et al. 2008

Laboratory Investigation

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112

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An understanding of the structure and composition of the myelin sheath is essential to understand the pathogenesis of demyelinating diseases such as multiple sclerosis (MS). The presence of citrulline in myelin proteins in particular myelin basic protein (MBP) causes an important change in myelin structure, which destabilizes myelin. The peptidylarginine deiminases (PADs) are responsible for converting arginine in proteins to citrulline. Two of these, PAD2 and PAD4, were localized to the myelin sheath by immunogold electron microscopy. Deimination of MBP by the recombinant forms of these enzymes showed that it was extensive, that is, PAD2 deiminated 18 of 19 arginyl residues in MBP, whereas PAD4 deiminated 14 of 19 residues. In the absence of PAD2 (the PAD2-knockout mouse) PAD4 remained active with limited deimination of arginyl residues. In myelin isolated from patients with MS, the amounts of both PAD2 and PAD4 enzymes were increased compared with that in normals, and the citrullinated proteins were also increased. These data support the view that an increase in citrullinated proteins resulting from increased PAD2 and 4 is an important change in the pathogenesis of MS. Peptidylarginine deiminases (PADs) are enzymes which deiminate arginyl residues in proteins. Five isozymes, termed PADs 1-4 and PAD6, are known, which have some tissue specificity, although PAD2 is widely distributed. 1 It is the principal PAD enzyme in brain, where it has been shown to be responsible for the deimination of arginyl residues in myelin basic protein (MBP), a principal protein in myelin 2 and a possible autoantigen in multiple sclerosis (MS). 3,4 The presence of other PAD enzymes in myelin has not been reported. For all PADs, the deimination reaction involves the conversion of arginyl residues in proteins to citrulline and the formation of ammonia. 5 The conversion of arginine to citrulline involves the loss of one positive charge from the protein for each arginine deiminated.In earlier studies, we reported that MBP isolated from white matter from normal human brain could be fractionated into several components by column chromatography. One of these components, which accounted for 20% of all the MBP, contained six citrullinyl residues, the sites of which we determined by protein sequencing. 6 More recently, the deimination has been shown to be more extensive by mass spectrometry with partial deimination of many arginines. 7 The loss of six positive charges accounted for the chromatographic behavior on the cation-exchange column. This same fraction isolated from patients with MS accounted for 45% of the total MBP, and in a case of fulminating MS, it accounted for 80-90% of all the MBP. 8 Instead of six arginyl residues in normal MBP, 6 18 of 19 arginyl residues in the Marburg's MBP were deiminated. In a number of in vitro studies in protein-lipid interaction systems, we showed that this deiminated protein was unable to compact lipid bilayers, causing destabilization, which might be the mechanism of demyelination. 9 Our recent studie...

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Section: Methodsmentioning

confidence: 99%

Section: Preparation Of Myelinmentioning

confidence: 99%

Myelin localization of peptidylarginine deiminases 2 and 4: comparison of PAD2 and PAD4 activities

Wood

Ackerley

Brand

et al. 2008

Laboratory Investigation

Self Cite

112

View full text Add to dashboard Cite

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“…Nervous system disorders PAD2 has been detected at high levels in the grey matter and hypothalamus [22], as well as in hippocampus, and in rat glial cells, especially astrocytes [23][24][25], microglial cells [10,25], and oligodendrocytes [26]. PAD4 has also been detected in extracts of mouse brain and spinal cord [27]. The brains of patients with multiple sclerosis (MS) show increased levels of deiminated myelin basic protein (MBP) and of deiminated glial fibrillary acidic protein (GFAP).…”

Section: Deimination In Non Cutaneous Diseasesmentioning

confidence: 99%

Peptidylarginine deiminases and deimination in biology and pathology: Relevance to skin homeostasis

Chavanas

Méchin

Nachat

et al. 2006

Journal of Dermatological Science

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“…Ishigami et al [57] identified glial fibrillary acidic protein (GFAP), a marker of astrocytes in the AD brain, to be a substrate for host PAD2, and suggested a role for the citrullinated GFAP in the progression of this neurodegenerative disease. GFAP deimination was characteristic for AD in humans and in experimental autoimmune encephalomyelitis (EAE) in mice where the BBB was breached [58–60]. Although not conclusively shown, citrullinated GFAP (dysfunctional protein) would link with defects in BBB integrity because the foot processes of astrocytes tightly cover capillary openings in the endothelial cell junctions to protect neurons from extrinsic insults.…”

Section: Introductionmentioning

confidence: 99%

Citrullination as a plausible link to periodontitis, rheumatoid arthritis, atherosclerosis and Alzheimer’s disease

Olsen

Singhrao

Potempa

2018

Journal of Oral Microbiology

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Periodontitis, rheumatoid arthritis (RA), atherosclerosis (AS), and Alzheimer’s disease (AD) are examples of complex human diseases with chronic inflammatory components in their etiologies. The initial trigger of inflammation that progresses to these diseases remains unresolved. Porphyromonas gingivalis is unique in its ability to secrete the P. gingivalis-derived peptidyl arginine deiminase (PPAD) and consequently offers a plausible and exclusive link to these diseases through enzymatic conversion of arginine to citrulline. Citrullination is a post-translational enzymatic modification of arginine residues in proteins formed as part of normal physiological processes. However, PPAD has the potential to modify self (bacterial) and host proteins by deimination of arginine amino acid residues, preferentially at the C-terminus. Migration of P. gingivalis and/or its secreted PPAD into the bloodstream opens up the possibility that this enzyme will citrullinate proteins at disparate body sites. Citrullination is associated with the pathogenesis of multifactorial diseases such as RA and AD, which have an elusive external perpetrator as they show epidemiological associations with periodontitis. Therefore, PPAD deserves some prominence as an external antigen, in at least, a subset of RA and AD cases, with as yet unidentified, immune/genetic vulnerabilities.

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Citrullination of central nervous system proteins during the development of experimental autoimmune encephalomyelitis

Cited by 45 publications

References 32 publications

Myelin localization of peptidylarginine deiminases 2 and 4: comparison of PAD2 and PAD4 activities

Myelin localization of peptidylarginine deiminases 2 and 4: comparison of PAD2 and PAD4 activities

Peptidylarginine deiminases and deimination in biology and pathology: Relevance to skin homeostasis

Citrullination as a plausible link to periodontitis, rheumatoid arthritis, atherosclerosis and Alzheimer’s disease

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