A Tale of Two Citrullines—Structural and Functional Aspects of Myelin Basic Protein Deimination in Health and Disease

Abstract

Myelin basic protein (MBP) binds to negatively charged lipids on the cytosolic surface of oligodendrocyte membranes and is responsible for adhesion of these surfaces in the multilayered myelin sheath. The pattern of extensive post-translational modifications of MBP is dynamic during normal central nervous system (CNS) development and during myelin degeneration in multiple sclerosis (MS), affecting its interactions with the myelin membranes and with other molecules. In particular, the degree of deimination (or citrullination) of MBP is correlated with the severity of MS, and may represent a primary defect that precedes neurodegeneration due to autoimmune attack. That the degree of MBP deimination is also high in early CNS development indicates that this modification plays major physiological roles in myelin assembly. In this review, we describe the structural and functional consequences of MBP deimination in healthy and diseased myelin.

Peptidylarginine deiminase 2 (PAD2) overexpression in transgenic mice leads to myelin loss in the central nervous system

“…The involvement of PAD in the pathogenesis of various autoimmune diseases such as rheumatoid arthritis has been established (Suzuki et al, 2003;Vossenaar et al, 2003a;Lundberg et al, 2005;Yamada et al, 2005). Given the increased citrullination of MBP and other proteins in MS (Kim et al, 2003) (reviewed in Harauz and Musse, 2007;Moscarello et al, 2007), we postulated that upregulation of PAD2 also represented an important early molecular change in demyelinating disease, and that increased citrullination of MBP results in reduced myelin stability in MS brain white matter (Moscarello et al, 1994). Evidence for PAD2 involvement has been obtained from the ND4 transgenic mouse model for demyelinating disease, in which increases in both PAD activity and mRNA levels were observed 1 month prior to an increase in citrullinated MBP and the concomitant appearance of any clinical or pathological signs (Moscarello et al, 2002a).…”

Contribution of Myelin Autoantigen Citrullination to T Cell Autoaggression in the Central Nervous System

“…The de novo recognition of self-Ags that have been modified as a result of pathophysiological disturbance (3,4) is an appealing basis for breakdown in immunologic self tolerance; namely, the immune system would target the modified self-Ag as if it were pathogen derived. The literature provides various examples of Ab-and/or T cell-reactivity against antigenic epitopes that contain PTM such as glycosylation, deamidation, and citrullination (5)(6)(7)(8). Citrullination, the deimination of Arg to citrulline (Cit) (9), has received particular interest as an autoantigen modification.…”

Apoptosis of Oligodendrocytes and Post-Translational Modifications of Myelin Basic Protein in Multiple Sclerosis: Possible Role for the Early Stages of Multiple Sclerosis

“…It is localized in the cytoplasm and interacts with lipid molecules of the cell membrane in order to form the compact structure of major dense line, seen in electron micrographs of myelin, by apposing the cytoplasmic faces of the membrane [29]. Further microheterogeneity of the 18.5-kDa molecule was suspected by the fact that several bands (6–8) resolved on alkaline-urea polyacrylamide gel electrophoresis (PAGE).…”

“…Further microheterogeneity of the 18.5-kDa molecule was suspected by the fact that several bands (6–8) resolved on alkaline-urea polyacrylamide gel electrophoresis (PAGE). Using CM52 cation exchange chromatography, several charge isomers are yielded, named C1-C8 where C1 or MBP-Cit0 is the least modified and most cationic, and C8 or MBP-Cit6 is the most modified and the least cationic [29]. The cause of this charge microheterogeneity is the conversion of arginine to citrulline (6 conversions from C1 to C8 molecule), reducing the charge by +1 and the mass by 1 Da [30].…”