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Molecular & Cellular Proteomics 2:453-462, 2003.
© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

Multiple Sclerosis

An Important Role for Post-Translational Modifications of Myelin Basic Protein in Pathogenesis^*

J. K. Kim, F. G. Mastronardi, D. D. Wood, D. M. Lubman, R. Zand^|| and M. A. Moscarello^,¶

From the Department of Chemistry, University of Michigan, Ann Arbor, MI 48109-1055, Structural Biology & Biochemistry, Research Institute, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada, and ^|| Biophysics Research Division and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109-1055

Myelin basic protein (MBP) represents a candidate autoantigen in multiple sclerosis (MS). We isolated MBP from normal and MS human white matter and purified six components (charge isomers) to compare the post-translational modifications on each. The sites and extent of methylation, deimination, and phosphorylation were documented for all tryptic peptides by mass spectrometry. We found that mono and dimethylated arginine 107 was increased in MS samples; deimination of arginine occurred at a number of sites and was elevated in MS; phosphorylation was observed in 10 peptides in normal samples but was greatly reduced or absent in most peptides from MS samples. Data obtained with MBP isolated from fresh brain obtained from a spontaneously demyelinating mouse model supported the view that the changes observed in human brain were probably related to pathogenesis of demyelination, i.e. we found decreased phosphorylation and decreased amounts of glycogen synthesis kinase in brain homogenates using specific antibodies. This study represents the first to define post-translational modifications in demyelinating disease and suggest an important role in pathogenesis.

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