Isoaspartic acid is present at specific sites in myelin basic protein from multiple sclerosis patients: could this
Michael G Friedrich1,2, Sarah E Hancock1,2, Mark J Raftery3
1Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, 2522, Australia.
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.
Insights
Multiple sclerosis (MS) involves immune system damage to myelin. This study found elevated isoaspartate, an abnormal protein modification, on myelin basic protein in MS patients, suggesting it may trigger an immune response and contribute to MS.
Area of Science:
- Neuroimmunology
- Proteomics
- Biochemistry
Background:
- Multiple sclerosis (MS) is an autoimmune disease characterized by myelin sheath damage in the central nervous system.
- The exact cause of MS remains unknown, but immune-mediated myelin destruction is a key feature.
- Myelin basic protein (MBP) is a major component of the myelin sheath.
Purpose of the Study:
- To investigate modifications in myelin basic protein (MBP) in patients with multiple sclerosis (MS).
- To identify specific sites of protein modification that may be characteristic of MS.
- To explore the potential role of these modifications in the etiology of MS.
Main Methods:
- Proteomic analysis of myelin basic protein (MBP) from the cerebellum of control and MS patients.
- Mass spectrometry and amino acid analysis were employed to detect protein modifications.
- Quantification of amino acid racemization, specifically aspartate (Asp), and isoaspartate (isoAsp) formation.
Main Results:
- Myelin basic protein (MBP) is a long-lived protein and exhibits extensive modifications.
- A significant increase in aspartate (Asp) racemization and isoaspartate (isoAsp) formation was observed in MBP from MS patients compared to controls.
- Two specific surface regions of MBP showed significantly elevated isoaspartate levels in MS patients.
Conclusions:
- The elevated levels of isoaspartate (isoAsp) in specific regions of myelin basic protein (MBP) in MS patients suggest a potential role in disease pathogenesis.
- The formation of isoaspartate can render peptides immunogenic, potentially eliciting an immune response against modified MBP.
- These findings implicate isoaspartate modification of MBP in the autoimmune processes underlying multiple sclerosis.
