Abstract
ObjectiveHere, we aimed to identify protein biomarkers that could rapidly and accurately diagnose multiple sclerosis (MS) using a highly sensitive proteomic immunoassay.MethodsTandem mass tag (TMT) quantitative proteomic analysis was performed to determine the differentially expressed proteins (DEPs) in cerebrospinal fluid (CSF) samples collected from 10 patients with MS and 10 non-inflammatory neurological controls (NINCs). The DEPs were analyzed using bioinformatics tools, and the candidate proteins were validated using the ELISA method in another cohort comprising 160 samples (paired CSF and plasma of 40 patients with MS, CSF of 40 NINCs, and plasma of 40 healthy individuals). Receiver operating characteristic (ROC) curves were used to determine the diagnostic potential of this method.ResultsCompared to NINCs, we identified 83 CSF-specific DEPs out of a total of 343 proteins in MS patients. Gene ontology (GO) enrichment analysis revealed that these DEPs are mainly involved in platelet degranulation, negative regulation of proteolysis, and post-translational protein modification. Pathway enrichment analysis revealed that the complement and coagulation cascades, Ras signaling pathway, and PI3K-Akt signaling pathway are the main components. Insulin-like growth factor-binding protein 7 (IGFBP7), insulin-like growth factor 2 (IGF2), and somatostatin (SST) were identified as the potential proteins with high scores, degree, and centrality in the protein-protein interaction (PPI) network. We validated the expression of these three proteins using ELISA. Compared to NINCs, the level of CSF IGFBP7 was significantly upregulated, and the level of CSF SST was significantly downregulated in the MS group.ConclusionOur results suggest that SST and IGFBP7 might be associated with the pathogenesis of MS and would be helpful in diagnosing MS. Since IGFBP7 was used to classify relapsing remitting MS (RRMS) and secondary progressive MS (SPMS) patients, therefore, it may act as a potential key marker and therapeutic target in MS.
Highlights
Multiple sclerosis (MS) is a chronic autoimmune demyelinating disorder of the central nervous system (CNS)
After analyzing node degree using this network, the top 10 proteins in the degree of the nodes in this network include: KNG1, C4A, Insulin-like growth factor-binding protein 7 (IGFBP7), PENK, CSF1, insulin-like growth factor 2 (IGF2), TGOLN2, IGFBP4, GOLM1, SST. In these top 10 proteins, IGF2, IGBP7 and SST were the proteins with large fold changes (FC=4.43, 2.60 and 0.17).Besides, we found that IGF2, IGFBP7 and SST are related to demyelinating disease in previous research [19,20,21]
Compared to NINCs, the level of CSF IGFBP7 was significantly upregulated, and the level of CSF SST was significantly downregulated in the MS group (Figures 4A, B)
Summary
Multiple sclerosis (MS) is a chronic autoimmune demyelinating disorder of the central nervous system (CNS). It is the main cause of severe neurological effects and disabilities in young adults [1]. An estimated 2.5 million people worldwide are affected with MS, and it is more common in women than in men [2]. MS is classified into four types based on disease presentation, which include clinically isolated syndrome (CIS), relapsing remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS). The majority of patients are affected with RRMS (85–90%); based on the statistics, over time, approximately half of these patients are prone to develop SPMS [3, 4]
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