Brain Extracellular Matrix implications in multiple neurological disorders are revealed through a meta-analysis of transcriptional changes

Abstract

AbstractNeurological disorders comprise a wide range of illnesses that may affect the central and peripheral nervous systems. Despite diverse etiologies, patients with these disorders may share symptoms.In this study, we aimed to explore potential common mechanisms between seven neurological disorders spanning three categories: neurodegenerative diseases, neuropsychiatric disorders, and neurodevelopmental disorders, by comparing gene expression profiles and focusing on the most prominent dysregulated genes consistently reported within and across disorders. Our results demonstrate 31 genes that are commonly differentially expressed in brain cells and tissues derived from human disease models when compared to healthy controls. These genes were enriched in brain Extracellular Matrix (ECM) pathways, Growth factor binding, Response to acid chemical, and External encapsulating structure. Remarkedly, dysregulation of ECM genes was evident separately in each of the three categories of disorders. This suggests a notable distinction in the brain ECM in disease states. Furthermore, we identified that the most frequently reported genes among all disorders wereGFAP, andIFITM3.Key PointsAnalysis of 41 human studies revealed 31 significantly dysregulated genes shared among seven neurological disorders when compared to healthy controls, spanning three distinct categories: Neurodegenerative diseases, Neuropsychiatric disorders, and Neurodevelopmental disorders.These shared Differentially Expressed Genes (DEGs) demonstrated significant enrichment for Extracellular Matrix (ECM) pathways, Growth factor binding, Response to acid chemical, Blood vessel development, and External encapsulating structure. Particularly,SSTandBCL6were the most frequently reported shared DEGs.Notably, each of the three categories of neurological disorders exhibited significant cellular component enrichment for ECM pathways.In order to distinguish noise genes (false-positive genes) from disease-relevant genes, we identified the DEGs that were reported the highest number of times per disorder.GFAP, followed byIFITM3, were found to be the most reported genes.Furthermore, due to partially shared symptoms, we explored commonalities between Autism Spectrum Disorders (ASD) and Schizophrenia. DEGs shared between both disorders were specifically enriched with ECM pathways, External encapsulating structure, Growth factor binding, Cell adhesion molecule binding, and PI3K-Akt signaling pathway. Noteworthy,IFITM2, HSPB1, IFITM3, HSPA1A, MKNK2, GFAPandCOL4A1were among the most frequently reported shared DEGs.The central aspects of our findings suggest a substantial distinction between the Central Nervous System (CNS) ECM in health and disease.