Integrated Blood Brain Transcriptomics Reveals CD79A and GRIA2 as Drug Repurposing Targets in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) has concomitant immune and neurodegenerative mechanisms that are not tractable to single{square}mechanism treatments. We speculated that simultaneous transcriptomic-network analysis of peripheral blood mononuclear cells (PBMCs) and MS brain lesions would identify convergent, druggable hubs susceptible to combination repurposing approaches. Microarray data of PBMCs (GSE21942; 14 MS, 15 controls) and brain lesions (GSE38010; 5 MS, 2 controls) were analyzed using differential{square}expression thresholds (adjusted P < 0.05; |log{square}FC| [&ge;] 1.5). Protein-protein{square}interaction networks were constructed with Search Tool for the Retrieval of Interacting Genes and subnetworks recognized by molecular complex detection. PBMC co{square}expression{square}modules were recognized by Weighted Gene Co-expression Network Analysis. Functional enrichments of cluster genes were undertaken by gene ontology and gene set enrichment analysis. CytoHubba identified candidate genes first, then hubs were identified by Least Absolute Shrinkage and Selection Operator (LASSO) regression (PBMCs) and top three brain lesion CytoHubba genes were considered hub genes. We screened a ligand library against four hubs CD79A, GRIN2A, NRXN1, and GRIA2, and assessed binding stability by 200 ns molecular dynamics and MM/PBSA. We found 142 PBMC differentially expressed genes (DEGs) and 1493 lesion DEGs, which were mapped to four peripheral modules B{square}cell{square}receptor signalling, erythrocyte metabolism, spliceosome stress and dampened innate sensing, and four central modules glutamatergic synapse, axon ensheathment/sodium{square}channel stress, netrin{square}1 signalling and nucleocytoplasmic{square}transport. LASSO identified FCRL1, CD22, and CD79A, while GRIN2A, GRIA2, and NRXN1 were the chosen brain hubs based on CytoHubba Maximal Clique Centrality. Molecular docking and dynamics simulation identified icotinib and niraparib as dual{square}target ligands of CD79A and GRIA2. Our end{square}to{square}end discovery pipeline defines CD79A and GRIA2 as dual{square}compartment targets. Repurposing compounds like icotinib and niraparib to co{square}modulate B{square}cell activation and excitotoxic synaptic injury represents an actionable strategy for multipronged treatments of MS.