Investigating the role of ncRNAs as therapeutic targets involved in ERK ̸ MAPK pathways through Major depressive disorder
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Setare Samizade,1,* Alireza Nasr Esfahani,2 Pegah Javid,3 Mansoureh Azadeh,4
1. 1Zist Fanavari Novin Biotechnology Department, Provincial Technical and vocational Training Organization, Isfahan, Iran
2. 1Zist Fanavari Novin Biotechnology Department, Provincial Technical and vocational Training Organization, Isfahan, Iran
3. 1Zist Fanavari Novin Biotechnology Department, Provincial Technical and vocational Training Organization, Isfahan, Iran
4. 1Zist Fanavari Novin Biotechnology Department, Provincial Technical and vocational Training Organization, Isfahan, Iran
- Introduction: Major depressive disorder is one of the most common neuropsychiatric diseases. Epigenetic
mechanisms can play a role in increasing depression risk following adverse life events that
provide a mechanism for integrating genetics and environmental factors. Epigenetics refers to
processes that affect gene expression and translation in which DNA sequence changes are not
involved while it includes methylation of DNA (mDNA), microRNAs (miRNAs), and long
non-coding RNAs (lncRNAs). Recently, miRNAs and lncRNAs have emerged as a novel class
of gene regulatory elements with conserved roles in development and disease. Thus, the
purpose of our study was to investigate the interaction between microRNAs, lncRNAs, and
gene expression in the pathway.
- Methods: The feature of microRNA was achieved from miRBase, human
disease database (HMDD), and miRdSNP databases. Target genes were identified by
investigation in miRTarBase and miRWalk databases. Venn diagram was used to identify the
shared target genes between miRNAs. The GSE54562 derived from the Gene Expression
Omnibus (GEO) datasets was analyzed to obtain potential therapeutic targets of MDD. The
differentially expressed genes (DEG) between MDD and normal tissue from human brain
anterior cingulate cortex were obtained using GEO2R. The gene ontology function and path
enrichment analysis were performed from Kyoto Encyclopedia of Genes and Genomes
(KEGG) to identify pathways and annotation functions of DEGs. LncRNAs associated with
overexpressed genes were found through LncRRIsearch and their relationship with depressive
disorder was investigated by LncRNADisease 2.0. The GeneMANIA database was used to
map the relationship between genes in the form of a gene network.
- Results: Through the bioinformatics
challenges in the current study, the hsa-miR-22-5p, hsa-miR-155-5p were found as the best
miRNAs, their target genome and associated cell-signaling pathways. The findings presented
that this miRNAs had a key role in both “ERK” and “MAPK” signaling pathways. . The result
demonstrated that hsa-miR-22-5p, hsa-miR-155-5p inhibit Ras by blocking Raf-1, MEK1/2
which active ERK and c-fos through phosphorylation in MAPK pathways. These microRNAs
inhibits (IL1b-IL6-IL15-lif-tnf) by blocking MKK4/7, JUNK1/2 in TNF pathway in MDD
patients.
- Conclusion: Increasing proof supports a critical role of
mitogen-activated protein kinases (MAPKs), specially the extracellular signal-regulated kinase
(ERK) subclass MAPK, in pathogenesis, symptomatology, and treatment of MDD in which
ERK signaling was significantly downregulated in the prefrontal cortex and hippocampus,
middle regions implicated in depression. Expression of phosphatases (MKP-1, MKP-2, PP1)
improved in the prefrontal cortex and hippocampus of depressed human or animals. Intracranial
injection of the MKP-1 inhibitor reversed the decreased hippocampal ERK phosphorylation
and decreased behavioral responses to stress. The lncRNAs can be diagnostic biomarkers for
MDD, we aimed to quantify the levels of DISC1 and DISC2 lncRNA transcripts. These facts
verified that DISC1 and DISC2 lncRNA expression relates to an improved danger of MDD
and can contain numerous molecular mechanisms. Our study discovered that the transcript
stages of DISC1 and DISC2 lncRNA can be taken into consideration as a great putative
biomarker for patients with MDD.
- Keywords: Depression disease, MAPK, MicroRNA, ERK, LncRNA
