Isoaspartic acid is present at specific sites in myelin basic protein from multiple sclerosis patients: could this represent a trigger for disease onset?

Abstract

Multiple sclerosis (MS) is associated with breakdown of the myelin sheath that coats neurons in the central nervous system. The cause of MS is not known, although the pathogenesis involves destruction of myelin by the immune system. It was the aim of this study to examine the abundant myelin protein, myelin basic protein (MBP), to determine if there are sites of modification that may be characteristic for MS. MBP from the cerebellum was examined from controls and MS patients across the age range using mass spectrometry and amino acid analysis. Amino acid racemization data indicated that myelin basic protein is long-lived and proteomic analysis of MBP showed it to be highly modified. A common modification of MBP was racemization of Asp and this was significantly greater in MS patients. In long-lived proteins, L-Asp and L-Asn can racemize to three other isomers, D-isoAsp, L-isoAsp and D-Asp and this is significant because isoAsp formation in peptides renders them immunogenic.Proteomic analysis revealed widespread modifications of MBP with two surface regions that are altered in MS. In particular, isoAsp was significantly elevated at these sites in MS patients. The generation of isoAsp could be responsible for eliciting an immune response to modified MBP and therefore be implicated in the etiology of MS.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0348-x) contains supplementary material, which is available to authorized users.

Identification of Novel Site-Specific Alterations in the Modification Level of Myelin Basic Protein Isolated from Mouse Brain at Different Ages Using Capillary Electrophoresis-Mass Spectrometry

“…Most of the modified peptides were present in very low amounts. Therefore, we were interested to examine possible alterations of the MBP modification status in older mice, as levels of MBP deamidation and citrullination are known to increase in aged humans and multiple sclerosis patients …”

“…A summary of significant modification sites of myelin basic protein is shown in Figure . The data has been compiled from Harauz and Boggs with addition of more recent data from Friedrich et al . The figure illustrates results from different species of different age and of healthy and diseased states comprising 53 modifications at 50 sites.…”

“…In this study we applied CE–MS using a neutrally coated capillary for in‐depth analysis of enzymatically digested MBP purified from mouse brain. A large number of modification sites known from human MBP were experimentally proved on mouse MBP for the first time …”

Molecular Processes Implicated in Human Age-Related Nuclear Cataract

“…In the cerebella of multiple sclerosis patients, MBP was found to have been degraded to a significantly greater extent at many sites 146 than was MBP from unaffected individuals. It has been proposed that this site-specific modification of MBP could be responsible for initiating the autoimmune response that is recognized clinically as multiple sclerosis.…”

“…A large proportion of Asp in MBP was discovered to be present in adults as a mixture of D-Asp and D-and L-isoAsp isomers. 146,147 The fact that nerve conductance and the operation of the brain continues despite large-scale degradation of axonal insulation is itself surprising. In this regard, it is analogous to the adult lens, which remains transparent despite a vast amount of PTM.…”