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MicroRNAs (miRNAs) are short non-coding RNAs with a 22 nucleotide sequence length and docks to the 3′UTR/5’UTR of the gene to regulate their mRNA translation to play a vital role in neurodegenerative diseases. The Nuclear Receptor gene (NR4A2), a transcription factor, and a steroid-thyroid hormone retinoid receptor is involved in neural development, memory formation, dopaminergic neurotransmission, and cellular protection from inflammatory damage. Therefore, recognizing the miRNAs is essential to efficiently target the 3′UTR/5’UTR of the NR4A2 gene and regulate neurodegeneration. Highly stabilized top miRNA-mRNA hybridized structures, their homologs, and identification of the best structures based on their least free energy were evaluated using  in silico  techniques. The miR-gene, gene-gene network analysis, miR-disease association, and transcription factor binding sites were also investigated. Results suggest top 166 miRNAs targeting the NR4A2 mRNA, but with a total of 10 miRNAs bindings with 100% seed sequence identity (both at 3’ and 5’UTR) at the same position on the NR4A2 mRNA region. The miR-373-3p and miR-520e-3p are considered the best candidate miRNAs hybridizing with high efficiency at both 3’ and 5’UTR of NR4A2 mRNA. This could be due to the most significant seed sequence length complementary, supplementary pairing, and absence of non-canonical base pairs. Furthermore, the miR-gene network, target gene-gene interaction analysis, and miR-disease association provide an understanding of the molecular, cellular, and biological processes involved in various pathways regulated by four transcription factors (PPARG, ZNF740, NRF1, and RREB1). Therefore, miR-373-3p, 520e-3p, and four transcription factors can regulate the NR4A2 gene involved in the neurodegenerative process.

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Structural, molecular hybridization and network based identification of miR-373-3p and miR-520e-3p as regulators of NR4A2 human gene involved in neurodegeneration