AUTHOR=Liu Lichun , Lai Yongxing , Zhan Zhidong , Fu Qingxian , Jiang Yuelian 

TITLE=Downregulation of Three Immune-Specific Core Genes and the Regulatory Pathways in Children and Adult Friedreich's Ataxia: A Comprehensive Analysis Based on Microarray

JOURNAL=Frontiers in Neurology

VOLUME=Volume 12 - 2021

YEAR=2022

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2021.816393

DOI=10.3389/fneur.2021.816393

ISSN=1664-2295

ABSTRACT=Background: Friedreich’s ataxia (FRDA) is a familial hereditary disorder that lacks available therapy. Therefore, Identification of novel biomarkers and key mechanisms related to FRDA progression is urgently demanded.
Methods: We identified the up-regulated and down-regulated differentially expressed genes (DEGs) in children and adult FRDA from GSE11204 dataset and intersected them to determine the co-expressed DEGs (co-DEGs). Enrichment analysis were conducted and a protein-protein interaction (PPI) network was constructed to identify key pathways and hub genes. The potential diagnostic biomarkers were validated using GSE30933 dataset. Cytoscape was applied to construct interaction and competitive endogenous RNA (ceRNA) networks.
Results: Gene Set Enrichment Analysis (GSEA) indicated that the genes in the children and adult samples were primarily enriched in immune-related functions. We identified 88 co-DEGs between children and adult FRDA samples. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome enrichment analysis suggested that these co-DEGs were primarily enriched in immune response, inflammatory reaction, and necroptosis. Immune infiltration analysis showed remarkable differences in the proportions of immune cell subtype between FRDA and normal samples. In addition, ten core genes and one gene cluster module were screened out based on PPI network. we verified eight immune-specific core genes using validation dataset and found CD28, FAS, and ITIF5 have high diagnostic significance in FRDA. Finally, NEAT1-hsa-miR-24-3p-CD28 and HOTAIR/NEAT1-hsa-miR-106b-5p/hsa-miR-93-5p-IFIT5 were identified as key regulatory pathways of children and adult FRDA.
Conclusions: Downregulation of three immune-specific hub genes, CD28, FAS, and IFIT5, as potential biomarkers for the diagnosis and treatment of FRDA in children and adults. Furthermore, NEAT1-hsa-miR-24-3p-CD28, HOTAIR-hsa-miR-106b-5p/hsa-miR-93-5p-IFIT5, and NEAT1-hsa-miR-106b-5p/hsa-miR-93-5p-IFIT5 may be potential RNA regulatory pathways related to the pathogenesis of children and adult FRDA.
Keywords: Friedreich’s ataxia, Biomarker, Hub genes, Bioinformatics, RNA regulatory pathways