WWW.JNEUROSCI.ORG
-
The Journal of Neuroscience Serious about science: Serious about timing
QUICK SEARCH:   [advanced]


     
-


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
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental data
Right arrow Submit an eLetter
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via ISI Web of Science (7)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mastronardi, F. G.
Right arrow Articles by Moscarello, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mastronardi, F. G.
Right arrow 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-{alpha} (TNF-{alpha}) protein. The elevated TNF-{alpha} 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-{alpha} may have been derived from astrocytes. In cell cultures of mouse and human oligodendroglial cell lines, PAD4 was predominantly cytosolic but TNF-{alpha} treatment induced its nuclear translocation. To address the involvement of TNF-{alpha} in targeting PAD4 to the nucleus, we found that transgenic mice overexpressing TNF-{alpha} 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-{alpha}; 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






-

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help
-
Copyright 2008 by Society for Neuroscience ONLINE ISSN: 1529-2401
-