Peptidyl argininedeiminase 2 CpG island in multiple sclerosis white matter is hypomethylated

Mastronardi, Fabrizio G.; Noor, Abdul; Wood, D. D.; Paton, Tara; Moscarello, Mario A.

doi:10.1002/jnr.21329

Cited by 172 publications

(119 citation statements)

References 62 publications

(81 reference statements)

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“…In a recent study, we have shown that the promoter of the PAD2 gene was hypomethylated on the CG sequences due to the over-activity of a DNA demethylase. 34 In the present work, we showed an increase in the number of PAD-labeled gold particles in myelin in MS. Therefore, upregulation of PAD2 by promoter hypomethylation and periaxonal localization with MBP may be prerequisites for myelin breakdown in a patchy distribution.…”

Section: Discussionsupporting

confidence: 64%

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: Discussionsupporting

confidence: 64%

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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“…PAD2 is a member of the PAD family of Ca 2ϩ -dependent enzymes, which catalyze the post-translational modification of protein arginines, in a process called deimination or citrullination (24). PAD2 expression and the level of citrullination correlate with active disease in both human MS and the animal models of MS (25)(26)(27)(28)(29)(30).…”

Section: Resultsmentioning

confidence: 99%

“…MS patients contain higher levels of MBP citrullination, which is thought to contribute to MBP degradation and loss of myelin sheath integrity (25)(26)(27)(28). Similarly, MBP citrullination and PAD2 activity correlate with disease in animal models of MS (29,30). Our studies demonstrate that both CNP and PAD2 interact with LRP1 CCRs as well as with the full-length LRP1.…”

Section: Multiple Sclerosis (Ms)mentioning

confidence: 99%

Identification of the Low Density Lipoprotein (LDL) Receptor-related Protein-1 Interactome in Central Nervous System Myelin Suggests a Role in the Clearance of Necrotic Cell Debris

Fernández-Castañeda

Arandjelovic

Stiles

et al. 2013

Journal of Biological Chemistry

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Background: LRP1 is a scavenger receptor involved in the clearance of apoptotic cells and myelin vesicles. Results: Novel ligands for LRP1 were discovered in CNS myelin by affinity purification combined with proteomics. Conclusion: Some ligands are intracellular proteins, suggesting a function for LRP1 in the clearance of necrotic debris. Significance: LRP1 mediates the removal of cellular waste and could maintain homeostasis.

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“…7 A decreased methylation of cytosine residues in the PADI2 promoter may explain the increased synthesis of the PADI2 protein in the white matter of patients with multiple sclerosis. 8 Taken together, these findings suggest that disturbances in PADI2 are likely to be related to the pathogenesis of neuropsychiatric diseases with neurodegenerative processes. PADI2 is located on chromosome 1p36.13, which has been suggested to be a candidate region for schizophrenia by some genome-wide linkage studies.…”

mentioning

confidence: 83%

A two-stage case–control association study of PADI2 with schizophrenia

et al. 2009

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Peptidylarginine deiminases (PADIs), five isoforms of which have been identified, catalyze the conversion of arginine residues to citrulline residues in proteins. Recent studies have revealed that abnormal activation of PADI2, the gene for which is expressed throughout the nervous system, is likely to be related to the pathogenesis of neuropsychiatric diseases with neurodegenerative processes, such as Alzheimer's disease and multiple sclerosis. Such a progressive neurodegenerative process could be involved in the etiology and/or course of schizophrenia, and PADI2 may be a candidate gene for schizophrenia. To assess whether PADI2 has a role in vulnerability to schizophrenia, we conducted a two-stage case-control association study in Japanese individuals. In a screening population of 534 patients and 559 control individuals, we examined eight single-nucleotide polymorphisms (SNPs) including four haplotype tag SNPs and four coding SNPs in PADI2. There was a potential association of a synonymous SNP in exon 7 with schizophrenia. However, we could not replicate this association in a confirmatory population of 2126 patients and 2228 control individuals. The results of this study suggest that PADI2 does not contribute to genetic susceptibility to schizophrenia.

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Peptidyl argininedeiminase 2 CpG island in multiple sclerosis white matter is hypomethylated

Cited by 172 publications

References 62 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

Identification of the Low Density Lipoprotein (LDL) Receptor-related Protein-1 Interactome in Central Nervous System Myelin Suggests a Role in the Clearance of Necrotic Cell Debris

A two-stage case–control association study of PADI2 with schizophrenia

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