Proteomics Comparison of Cerebrospinal Fluid of Relapsing Remitting and Primary Progressive Multiple Sclerosis

Abstract

BackgroundBased on clinical representation of disease symptoms multiple sclerosis (MScl) patients can be divided into two major subtypes; relapsing remitting (RR) MScl (85–90%) and primary progressive (PP) MScl (10–15%). Proteomics analysis of cerebrospinal fluid (CSF) has detected a number of proteins that were elevated in MScl patients. Here we specifically aimed to differentiate between the PP and RR subtypes of MScl by comparing CSF proteins.Methodology/Principal FindingsCSF samples (n = 31) were handled according to the same protocol for quantitative mass spectrometry measurements we reported previously. In the comparison of PP MScl versus RR MScl we observed a number of differentially abundant proteins, such as protein jagged-1 and vitamin D-binding protein. Protein jagged-1 was over three times less abundant in PP MScl compared to RR MScl. Vitamin D-binding protein was only detected in the RR MScl samples. These two proteins were validated by independent techniques (western blot and ELISA) as differentially abundant in the comparison between both MScl types.Conclusions/SignificanceThe main finding of this comparative study is the observation that the proteome profiles of CSF in PP and RR MScl patients overlap to a large extent. Still, a number of differences could be observed. Protein jagged-1 is a ligand for multiple Notch receptors and involved in the mediation of Notch signaling. It is suggested in literature that the Notch pathway is involved in the remyelination of MScl lesions. Aberration of normal homeostasis of Vitamin D, of which approximately 90% is bound to vitamin D-binding protein, has been widely implicated in MScl for some years now. Vitamin D directly and indirectly regulates the differentiation, activation of CD4+ T-lymphocytes and can prevent the development of autoimmune processes, and so it may be involved in neuroprotective elements in MScl.

Biomarkers of disease activity in multiple sclerosis

“…As more targeted therapies become available, rational treatment using biomarkers of disease activity may become useful in predicting responsiveness to different treatment options and guiding when changes in therapy are warranted to prevent relapses and accumulation of permanent disability (Table 1). Biomarkers may also be useful in characterizing different disease states, for example, proteomics analysis has found different protein expression in primary progressive compared to relapsing remitting MS [2]. Reliable biomarkers that help guide treatment decisions to prevent eventual disability have the potential to vastly improve outcomes and cost-effective care.…”

Discovery of Novel Disease-specific and Membrane-associated Candidate Markers in a Mouse Model of Multiple Sclerosis

“…Differential gene and protein expression profiles have been generated based on comparative analyses of healthy control and disease-affected tissues derived from clinical samples (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) and animal models (19 -29). These biomarker discovery platforms include gel-based approaches such as two-dimensional gel electrophoresis (2D-GE) (10,17,30), 2D-difference image gel electrophoresis (2D-DIGE) (9,14), as well as shotgun proteomics techniques (11,13,16,31,32) incorporating the use of label-free or stable isotope labeling LC-MS-based strategies for quantitative proteomic studies. In recent years there has been exponential growth in the use of these alternative gel-free shotgun proteomics strategies, which has been facilitated by advances in mass spectrometry instrumentation and computational capabilities.…”

Vitamin D in the healthy and inflamed central nervous system: access and function

“…The data on DBP levels in progressive MS is also conflicting. One study reported elevated DBP levels in CSF from both RRMS and secondary progressive MS [42], whereas another study did only detect DBP in CSF from patients with RRMS and not from primary progressive MS [43]. These conflicting results could reflect differences in sampling or analyzing methods, but also the relatively small sample sizes and the inclusion of specific MS phenotypes in some of these studies.…”