Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder observed due to the loss of motor neurons which control voluntary actions of the body. Four genes (superoxide dismutase 1 [SOD1], chromosome 9 open reading frame 72 [C9ORF72], TAR DNA-binding protein 43 [TARDBP], and fused in sarcoma [FUS]) were considered high-risk genes, associated with about 70% of familial ALS (fALS) cases. Molecules such as transcription factors (TFs) and post-transcriptional regulators microRNAs (miRNA) help to elucidate the expression level of genes and their regulation mechanisms. In this study, a constructed combinatorial regulatory network of ALS high-risk genes regulated by common miRNA targets and TFs. Three coherent and four incoherent feed-forward loops (FFLs) using a 3-node motif relationship (Gene-miRNAs-TFs) were identified. Two miRNAs (miR-3163 and miR-4422) were transcriptionally regulated by four (CEBPD, EGR1, SP1, and TBP) TFs, in which (CEBPD, EGR1, and SP1) upregulate the SOD1, whereas TBP downregulates the FUS. The miRNA expression data showed that miR-422 is highly expressed in the brain and high-risk genes were more expressed in the frontal cortex and cerebellum regions. Enrichment analysis showed miRNAs majorly associated with neurons. The results of this study highlighted the importance of regulatory molecules such as TFs and miRNA that control the functionality of genes simultaneously. Single TF or miRNA is able to control more than one gene, as shown in terms of FFLs important for regulation inside the cell. In future, in vitro and in vivo biochemical studies of the observed potential regulators could reveal further information about their role in the pathogenesis of ALS and could be used as therapeutic targets.
Key words: ALS, SOD1, C9ORF72, TARDBP, FUS, miRNAs, Transcription factors
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