QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, November 1, 2006, 26(44):11387-11396; doi:10.1523/JNEUROSCI.3349-06.2006

This Article Full Text Full Text (PDF) Supplemental data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (13) Citing Articles via Google Scholar Google Scholar Articles by Mastronardi, F. G. Articles by Moscarello, M. A. Search for Related Content PubMed PubMed Citation Articles by Mastronardi, F. G. Articles by Moscarello, M. A.

 Previous Article  |  Next Article 

Neurobiology of Disease
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

Fabrizio G. Mastronardi,¹ D. Denise Wood,¹ Jiang Mei,³ Reinout Raijmakers,⁴ Vivian Tseveleki,⁵ Hans-Michael Dosch,² Lesley Probert,⁵ Patrizia Casaccia-Bonnefil,³ and Mario A. Moscarello¹

¹Department of Structural Biology and Biochemistry and ²Infection, Immunity, Injury, and Repair, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8, ³Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, ⁴Department of Biochemistry, Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen, NL-6500 HB Nijmegen, The Netherlands, and ⁵Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens GR-115 21, Greece

Correspondence should be addressed to Fabrizio G. Mastronardi, Department of Structural Biology and Biochemistry, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8. Email: fabrizio{at}sickkids.ca

Modification of arginine residues by citrullination is catalyzed by peptidylarginine deiminases (PADs), of which five are known, generating irreversible protein structural modifications. We have shown previously that enhanced citrullination of myelin basic protein contributed to destabilization of the myelin membrane in the CNS of multiple sclerosis (MS) patients. We now report increased citrullination of nucleosomal histones by PAD4 in normal-appearing white matter (NAWM) of MS patients and in animal models of demyelination. Histone citrullination was attributable to increased levels and activity of nuclear PAD4. PAD4 translocation into the nucleus was attributable to elevated tumor necrosis factor- (TNF-) protein. The elevated TNF- in MS NAWM was not associated with CD3⁺ or CD8⁺ lymphocytes, nor was it associated with CD68⁺ microglia/macrophages. GFAP, a measure of astrocytosis, was the only cytological marker that was consistently elevated in the MS NAWM, suggesting that TNF- may have been derived from astrocytes. In cell cultures of mouse and human oligodendroglial cell lines, PAD4 was predominantly cytosolic but TNF- treatment induced its nuclear translocation. To address the involvement of TNF- in targeting PAD4 to the nucleus, we found that transgenic mice overexpressing TNF- also had increased levels of citrullinated histones and elevated nuclear PAD4 before demyelination. In conclusion, high citrullination of histones consequent to PAD4 nuclear translocation is part of the process that leads to irreversible changes in oligodendrocytes and may contribute to apoptosis of oligodendrocytes in MS.

Key words: multiple sclerosis; citrulline; peptidylarginine deiminase; myelin; TNF-; histone

---

Received June 2, 2006; revised Sept. 21, 2006; accepted Sept. 22, 2006.

Correspondence should be addressed to Fabrizio G. Mastronardi, Department of Structural Biology and Biochemistry, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8. Email: fabrizio{at}sickkids.ca

This article has been cited by other articles:

				Q. Li, Q. Ke, and M. Costa Alterations of histone modifications by cobalt compounds Carcinogenesis, July 1, 2009; 30(7): 1243 - 1251. [Abstract] [Full Text] [PDF]

				E H Halvorsen, E A Haavardsholm, S Pollmann, A Boonen, D van der Heijde, T K Kvien, and O Molberg Serum IgG antibodies to peptidylarginine deiminase 4 predict radiographic progression in patients with rheumatoid arthritis treated with tumour necrosis factor-{alpha} blocking agents Ann Rheum Dis, February 1, 2009; 68(2): 249 - 252. [Abstract] [Full Text] [PDF]

				A. A. Musse, Z. Li, C. A. Ackerley, D. Bienzle, H. Lei, R. Poma, G. Harauz, M. A. Moscarello, and F. G. Mastronardi Peptidylarginine deiminase 2 (PAD2) overexpression in transgenic mice leads to myelin loss in the central nervous system Dis. Model. Mech., November 1, 2008; 1(4-5): 229 - 240. [Abstract] [Full Text] [PDF]

				P. Proost, T. Loos, A. Mortier, E. Schutyser, M. Gouwy, S. Noppen, C. Dillen, I. Ronsse, R. Conings, S. Struyf, et al. Citrullination of CXCL8 by peptidylarginine deiminase alters receptor usage, prevents proteolysis, and dampens tissue inflammation J. Exp. Med., September 1, 2008; 205(9): 2085 - 2097. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help