Multiple sclerosis: an important role for post-translational modifications of myelin basic protein in pathogenesis

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...

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Bibliographic Details
Published in:Molecular & cellular proteomics 2003-07, Vol.2 (7), p.453-462
Main Authors: Kim, J K, Mastronardi, F G, Wood, D D, Lubman, D M, Zand, R, Moscarello, M A
Format: Article
Language:English
Subjects:
Animals
Arginine - metabolism
Brain - enzymology
Brain - metabolism
Case-Control Studies
Glycogen Synthase Kinases - biosynthesis
Humans
Mice
Mice, Transgenic
Multiple Sclerosis - etiology
Multiple Sclerosis - metabolism
Multiple Sclerosis - pathology
Myelin Basic Protein - chemistry
Myelin Basic Protein - isolation & purification
Myelin Basic Protein - metabolism
Phosphorylation
Protein Isoforms - chemistry
Protein Isoforms - metabolism
Protein Processing, Post-Translational
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Summary: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.
ISSN:1535-9476
1535-9484
DOI:10.1074/mcp.M200050-MCP200