Myelin in multiple sclerosis is developmentally immature.

Moscarello, Mario A.; Wood, D. D.; Ackerley, Cameron; Boulias, Chris

doi:10.1172/jci117300

Cited by 303 publications

(301 citation statements)

References 38 publications

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“…6,8,32 With each arginine deiminated, one positive charge is lost from MBP, which compromises its ability to interact with phospholipids of the myelin sheath, resulting in less compact myelin being more easily degraded. These observations have led us to postulate that citrullinated MBP represents an important component in the pathogenesis of MS. 4 The mechanism by which arginine is converted to citrulline in proteins involves a family of enzymes, the peptidylarginine deiminases, of which five isoforms are known.…”

Section: Discussionmentioning

confidence: 99%

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

Wood

Ackerley

Brand

et al. 2008

Laboratory Investigation

111

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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: Discussionmentioning

confidence: 99%

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

Wood

Ackerley

Brand

et al. 2008

Laboratory Investigation

111

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“…While the citrullinated form normally accounts for approximately 20% of the total MBP in a healthy human brain, in MS patients, the proportion has been found to be increased to 45%. 33 In the case of fulminant MS 100-fold higher level than the normal cytosolic Ca 2+ concentration (~10 -8 -10 -6 M). Moreover, in vitro, PAD2 is known to be activated at millimolar Ca 2+ concentrations.…”

Section: Peptidylarginine Deiminase and Protein Citrullination In Primentioning

confidence: 97%

“…Increased PAD expression and protein citrullination are commonly observed in several neurodegenerative diseases, including MS, AD, optic glaucoma and Parkinson disease, and in psoriasis, rheumatoid arthritis (RA) and cancer. [4][5][6][7]20,[31][32][33][34] In AD patients, the abnormal accumulation of citrullinated proteins and increased PAD2 expression are seen in the hippocampus, where vimentin and GFAP have been identified as PAD substrates. 6 Citrullinated proteins have also been observed in the cytoplasm of the substantia nigra dopamine neurons in Parkinson disease patients.…”

Section: Peptidylarginine Deiminase and Protein Citrullination In Primentioning

confidence: 99%

“…36 However, in other neurological disorders, including AD, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis, the citrullinated form remained at 20% of the total. 33 A biochemical study revealed that the rates of digestion of human MBPs containing 6 citrulline residues and 18 citrulline residues by cathepsin D were 4-fold and 45-fold, respectively, more rapid than the rate of digestion of non-citrullinated MBP. 37 Increasing the number of citrulline residues in MBP results in a more open conformation, decreases the charge and allows better access of the Phe-Phe linkages to cathepsin D, 38 thus, yielding much less compact protein-lipid complexes leading to a looser structure of the myelin sheath.…”

Section: Peptidylarginine Deiminase and Protein Citrullination In Primentioning

confidence: 99%

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Peptidylarginine deiminase and protein citrullination in prion diseases

Jang

Ishigami

Maruyama

et al. 2013

Prion

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“…In addition, the accumulation of citrullinated proteins has been described at sites of inflammation, including the joints of patients with all forms of arthritis (17), the brains of patients with multiple sclerosis (18) or Alzheimer's disease (19), and in the muscle fibers of patients with myositis (20). Hence, citrullinated proteins are present in the setting of both health and disease, while tolerance to citrullinated proteins appears to be selectively lost in patients with RA.…”

mentioning

confidence: 99%

Antibodies to citrullinated α‐enolase peptide 1 are specific for rheumatoid arthritis and cross‐react with bacterial enolase

Lundberg

Kinloch

Fisher

et al. 2008

Arthritis & Rheumatism

339

313

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Objective. To map the antibody response to human citrullinated ␣-enolase, a candidate autoantigen in rheumatoid arthritis (RA), and to examine crossreactivity with bacterial enolase.Methods. Serum samples obtained from patients with RA, disease control subjects, and healthy control subjects were tested by enzyme-linked immunosorbent assay (ELISA) for reactivity with citrullinated ␣-enolase peptides. Antibodies specific for the immunodominant epitope were raised in rabbits or were purified from RA sera. Cross-reactivity with other citrullinated epitopes was investigated by inhibition ELISAs, and cross-reactivity with bacterial enolase was investigated by immunoblotting.Results. An immunodominant peptide, citrullinated ␣-enolase peptide 1, was identified. Antibodies to this epitope were observed in 37-62% of sera obtained from patients with RA, 3% of sera obtained from disease control subjects, and 2% of sera obtained from healthy control subjects. Binding was inhibited with homologous peptide but not with the arginine-containing control peptide or with 4 citrullinated peptides from elsewhere on the molecule, indicating that antibody binding was dependent on both citrulline and flanking amino acids. The immunodominant peptide showed 82% homology with enolase from Porphyromonas gingivalis, and the levels of antibodies to citrullinated ␣-enolase peptide 1 correlated with the levels of antibodies to the bacterial peptide (r 2 ‫؍‬ 0.803, P < 0.0001). Affinitypurified antibodies to the human peptide cross-reacted with citrullinated recombinant P gingivalis enolase.Conclusion. We have identified an immunodominant epitope in citrullinated ␣-enolase, to which antibodies are specific for RA. Our data on sequence similarity and cross-reactivity with bacterial enolase may indicate a role for bacterial infection, particularly with P gingivalis, in priming autoimmunity in a subset of patients with RA.

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Myelin in multiple sclerosis is developmentally immature.

Cited by 303 publications

References 38 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 deiminase and protein citrullination in prion diseases

Antibodies to citrullinated α‐enolase peptide 1 are specific for rheumatoid arthritis and cross‐react with bacterial enolase

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