Research Article

Laboratory Investigation (2008) 88, 354–364; doi:10.1038/labinvest.3700748; published online 28 January 2008

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

Dorothy D Wood1, Cameron A Ackerley2, Ben van den Brand1, Li Zhang1, Reinout Raijmakers3, Fabrizio G Mastronardi1 and Mario A Moscarello1

  1. 1Molecular Structure and Function, The Hospital for Sick Children, Toronto, ON, Canada
  2. 2Department of Pathology, The Hospital for Sick Children, Toronto, ON, Canada
  3. 3Department of Biomolecular Chemistry, Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands

Correspondence: Dr MA Moscarello, Molecular Structure and Function, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. E-mail: mam@sickkids.ca

Received 17 October 2007; Revised 3 December 2007; Accepted 10 December 2007; Published online 28 January 2008.

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Abstract

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.

Keywords:

peptidylarginine deiminase, citrullinated myelin basic protein, myelin, multiple sclerosis, neurodegenerative disease

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