MicroRNAS Role as glutamate receptor 5 inhibitor in PI3K/Akt/mTOR Pathway in Huntington's disease

MicroRNAS Role as glutamate receptor 5 inhibitor in PI3K/Akt/mTOR Pathway in Huntington's disease
Setare Samizade,^1,* Alireza Nasr Esfahani,²
1. Islamic Azad University, Department of Biology, Falavarjan Branch, Isfahan, Iran
2. Islamic Azad University, Department of Biology, Falavarjan Branch, Isfahan, Iran
Introduction: Huntington’s disease (HD) is an adult-onset, inherited autosomal dominant neurodegenerative disorder caused by a polyglutamine (CAG) repeat expansion in exon 1 that encodes the amino-terminal of the huntingtin protein. Recently, microRNAs (miRNAs) have emerged as a novel class of gene regulatory elements with conserved roles in development and disease .so the purpose of our study is to investigate the relationship between microRNAs and CREB in PI3K/Akt/mTOR pathway.
Methods: The feature of microRNA was archived by using miRBase, HMDD and miRdSNP. Valid target genes and predict one were identified by miRTarBase, MIRWALK2.0, TargetScan and DIANA Tools. Venn diagram used to identify common target genes between MiRNAs .Gene expression in brain was obtained from The Human Protein Atlas. Finally, the pathway enrichment analysis was performed by the KEGG, David path. GENEMANIA used to find gene network.
Results: The result indicated that hsa- miR-1324, hsa-miR-185-5p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-24-3p and hsa- miR-573 inhibit MAPK3 by blocking RAS which active ERK5 and MEK5 by phosphorylation. Mentioned microRNAs activate NF‐κβ by inhibiting AKT, PDPK1 and PIK3CD in neurotrophin pathway and prevent Huntington development. Metabotropic glutamate receptor 5 (mGluR5) which is inhibited in PI3K/Akt/mTOR signaling resulting in ULK1 activation and the initiation of autophagy. Canonical mTOR signaling is initiated following receptor- dependent activation of PI3K to phosphorylate PDK1.
Conclusion: the inhibition of mGluR5 using CTEP, a selective negative allosteric mGluR5 modulator, can delay disease progression. Finally hsa-miR-1324, hsa-miR-185-5p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-24-3p and hsa-miR-573 by acting as NF‐κβ activator, prevent Huntington progression.
Keywords: Huntington’s disease, PI3K/Akt/mTOR Pathway, MicroRNA, Metabotropic glutamate receptor 5 (mGluR5)