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The delta opioid peptide D‐Alanine 2, Leucine 5 Enkephaline (DADLE)‐induces neuroprotection through cross‐talk between the UPR and pro‐survival MAPK‐NGF‐Bcl2 signaling pathways via modulation of several micro‐RNAs in SH‐SY5Y cells subjected to ER stress
Author(s) -
Moghal Erfath Thanjeem Begum,
Venkatesh Katari,
Sen Dwaipayan
Publication year - 2018
Publication title -
cell biology international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.932
H-Index - 77
eISSN - 1095-8355
pISSN - 1065-6995
DOI - 10.1002/cbin.10923
Subject(s) - dadle , unfolded protein response , neuroprotection , microbiology and biotechnology , endoplasmic reticulum , mapk/erk pathway , signal transduction , phosphorylation , opioid peptide , biology , chemistry , neuroscience , opioid , receptor , biochemistry
Parkinson's disease (PD) is the second most progressive neurodegenerative disease characterized by the loss of dopaminergic neurons and accumulation of misfolded proteins in endoplasmic reticulum (ER) leading to activation of the unfolded protein response (UPR). In the present study, we aimed to determine the potential survival effect of the delta opioid neuro‐peptide D‐Alanine 2, Leucine 5 Enkephaline (DADLE), and its mechanism in dopaminergic SH‐SY5Y cells which were subjected to ER stress. In this cellular model of PD, enhanced cell survivability was observed on DADLE treatment (but not with μ and κ opioid agonists) along with concomitant down regulation of the UPR stress sensors and protein aggregates. The study found increased phosphorylation of MEK‐1, which leads to activation of MAP kinase as well as enhanced expression of the pro‐survival gene nerve growth factor and anti‐apoptotic marker Bcl2. DADLE treatment could also significantly inhibit expression of the pro‐apoptotic marker BIM. Next‐generation sequence analysis revealed 93 micro (mi) RNAs to be differentially regulated following DADLE treatment in cells subjected to ER stress. Pathway prediction and previously published reports revealed that out of these 93 miRNAs, 34 can play a role in promoting cell survival. Specific modulation of two such miRNAs, namely miR‐30c‐2‐3p and miR‐200c, could partially reverse the positive survival effect induced by DADLE. Apart from the known miRNAs, various novel miRNAs were also observed following DADLE treatment which could also play a role in enhancing the survival of SH‐SY5Y cells under ER stress.