Integrated Bioinformatics Analysis of Shared Genes, miRNA, Biological Pathways and Their Potential Role as Therapeutic Targets in Huntington’s Disease Stages

Abstract

Huntington’s Disease (HD) is a progressive neurodegenerative disease caused by CAG repeat expansion in the huntingtin gene (HTT). The HTT gene was the first disease-associated gene mapped to a chromosome, but the pathophysiological mechanisms, genes, proteins or miRNAs involved in HD remain poorly understood. Systems bioinformatics approaches can divulge the synergistic relationships of multiple omics data and their integration, and thus provide a holistic approach to understanding diseases. The purpose of this study was to identify the differentially expressed genes (DEGs), HD-related gene targets, pathways and miRNAs in HD and, more specifically, between the pre-symptomatic and symptomatic HD stages. Three publicly available HD datasets were analysed to obtain DEGs for each HD stage from each dataset. In addition, three databases were used to obtain HD-related gene targets. The shared gene targets between the three public databases were compared, and clustering analysis was performed on the common shared genes. Enrichment analysis was performed on (i) DEGs identified for each HD stage in each dataset, (ii) gene targets from the public databases and (iii) the clustering analysis results. Furthermore, the hub genes shared between the public databases and the HD DEGs were identified, and topological network parameters were applied. Identification of HD-related miRNAs and their gene targets was obtained, and a miRNA-gene network was constructed. Enriched pathways identified for the 128 common genes revealed pathways linked to multiple neurodegeneration diseases (HD, Parkinson’s disease, Spinocerebellar ataxia), MAPK and HIF-1 signalling pathways. Eighteen HD-related hub genes were identified based on network topological analysis of MCC, degree and closeness. The highest-ranked genes were FoxO3 and CASP3, CASP3 and MAP2 were found for betweenness and eccentricity and CREBBP and PPARGC1A were identified for the clustering coefficient. The miRNA-gene network identified eleven miRNAs (mir-19a-3p, mir-34b-3p, mir-128-5p, mir-196a-5p, mir-34a-5p, mir-338-3p, mir-23a-3p and mir-214-3p) and eight genes (ITPR1, CASP3, GRIN2A, FoxO3, TGM2, CREBBP, MTHFR and PPARGC1A). Our work revealed that various biological pathways seem to be involved in HD either during the pre-symptomatic or symptomatic stages of HD. This may offer some clues for the molecular mechanisms, pathways and cellular components underlying HD and how these may act as potential therapeutic targets for HD.