Dysregulation of miRNA and its reversal with l-ascorbic acid during AGE-BSA induced ER stress in Mus musculus neuronal cells

Abstract

Loss of function and progressive death of neurons, the pathological mechanism of neurodegenerative diseases (NDDs) can occur as a result of apoptotic unfolded protein response (UPR) signaling induced by endoplasmic reticulum (ER) stress resulting from misfolded protein accumulation in ER lumen. Non-enzymatic glycation of proteins have been implicated in the pathophysiology of NDDs and are known to cause cellular oxidative stress leading to ER stress mediated neuronal apoptosis. MicroRNAs (miRNAs), post transcriptional regulators of gene expression are identified as regulators of UPR and the altered brain miRNA profiles in NDDs suggest the involvement of miRNA dysregulation in neuronal death. l-ascorbic acid, a micro nutrient and an important neuroprotectant has been suggested to be a modulator of gene expression. However there are few reports on miRNAs targeting the genes involved in neuronal apoptotic UPR signaling as well as l-ascorbic acid mediated regulation of neuronal UPR pathway and miRNA expression. Here, we identified a statistically significant downregulation of 7 miRNAs such as mmu-miR-24, 27b, 124, 224, 290, 351 and 488 and inverse expression relationship with their UPR related targets such as Perk, Ire1α, Chop and Puma during advanced glycated BSA (AGE-BSA) induced ER stress in Mus musculus cortical and hippocampal neurons. We also observed that a pretreatment with l-ascorbic acid alleviated AGE-BSA induced neuronal ER stress as well as the downregulation of the 7 potential miRNAs.