Assessing the Role of Citrullination and Lipid Interaction with Myelin Basic Protein in Multiple Sclerosis Etiology
Multiple sclerosis is believed to be an autoimmune disease and reflects a chronic state of inflammation. The etiology of the disease is incomplete and the diagnosis and prognosis remains a considerable challenge. In the search for biomarkers, the role of Peptidylarginine Deiminases, Myelin Basic Protein (MBP) and fatty acid metabolism, have been suggested essential for understanding disease initiation and progression. Peptidylarginine Deiminases are responsible for converting arginine to citrulline residues, which are known to be an immune response activating site when exposed to the immune system. MBP commonly contains six citrulline sites, but can contain up to 18 sites in hypercitrullinated form. Citrulline residues are considered important for the structure of MBP and its ability to form organised complexes with lipids, which are essential for the structure of the myelin sheet. When MBP is citrullinated the charge from arginine is neutralized resulting in a more open conformational structure of the protein, which has been shown to increase the rate of formation of complexes with lipids. The underlying mechanisms resulting in formation of these complexes and the exact role of citrullination have never been fully determined.
This project seeks to investigate more of the etiology behind Multiple Sclerosis focusing on the role of citrullination, the interaction between MBP and lipids as well as how regulation of the lipid metabolism potentially affect formation of the complexes with the lipids.
The analysis will be based on both a target and discovery based approaches using Mass spectrometry.
On the hypothesis that lipidation of MBP shield the immunogenic citrulline(s), the interaction between MBP and Lipids will be investigated including the influence of post translational modification on this interaction. A novel hypothesis considering the possibility of the lipids being covalently bond to MBP will be tested using Mass spectrometry. To ensure detection, synthetic lipidated peptides have already been analysed both using MALDI-TOF MS/MS and LC MS/MS, showing the lipidated peptides were MS analysis compatible.
Expanding the knowledge of the role of citrullination in Multiple sclerosis and examination of hypothesises will tribute to the understanding of the disease etiology and potentially provide retrospective information leading to diagnostic and prognostic biomarker discovery and potential target molecules for novel drug discovery.