MicroRNA-124 Reduces Arsenic-induced Endoplasmic Reticulum Stress and Neurotoxicity and is Linked with Neurodevelopment in Children

Abstract

Arsenic (As) exposure adversely affects neurodevelopment in children. Accumulation of misfolded proteins in cells exposed to As leads to endoplasmic reticulum (ER) stress response, which, if not relieved, results in cell death. Despite the potential role of ER stress for As-induced neurotoxicity, the underlying mechanisms remain poorly understood. Here we aimed to investigate the roles of microRNA(miR)-124, a novel ER stress suppressor, in As-induced ER stress response and cytotoxicity in neural cells. We further aimed to link these in vitro findings to neurodevelopmental outcomes in children who were exposed to As. Using Quantitative RT-PCR and Cyquant assay, we showed that miR-124 protects against As-induced cytotoxicity in neural cells with concomitant suppression of As-induced ER stress. In addition, As-induced cytotoxicity was exacerbated in miR-124 knockout cells generated by CRISPR-based gene editing compared scramble control. Furthermore, we identified two miR-124 SNPs rs67543816 (p = 0.0003) and rs35418153 (p = 0.0004) that are significantly associated with a mental composite score calculated from the Bayley Scales of Infant Development III in Bangladesh children. Our study reveals As-induced ER stress as a crucial mechanism underlying the toxic effects of As on neural cell function and neurodevelopment and identifies miR-124 as a potential preventative and therapeutic target against detrimental effects of As exposure in children. Exposure to arsenic (As) has been a serious public health concern because it has been attributed to myriad human diseases. Especially, As exposure during early brain development has persistent effects on neurocognitive function. Multiple epidemiologic studies report that As exposure is associated with neurocognitive deficits in children 1-10. For example, maternal and child urinary As levels inversely predicted performance IQ and verbal IQ, respectively, among Bangladesh children 2. Furthermore, elevated drinking water As levels adversely impacted IQ in children 10. Animal studies also confirmed the adverse impact of As on neurobehavioral and cognitive functions 11-15. Although epidemiological and animal studies have clearly established the neurotoxicity of As, the molecular mechanisms by which As impairs neuronal functions remain poorly understood. As can cause protein misfolding and induces stress response in the endoplasmic reticulum (ER), a multi-functional organelle essentiall for synthesis, folding, and processing of proteins 16-18. ER stress has arisen as a potential mechanism for As-induced neurotoxicity 19-23. A toxic inorganic species arsenite (As(III)) can react with thiols, leading the inhibition of protein function and misfolding 24,25. As-induced ER stress then triggers unfolded protein response (UPR) to restore ER homeostasis, mediated by three ER transmembrane receptors, including inositol-requiring protein-1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6) 16. However, excessive ER stress, if not resolved, leads to ...

Mechanistic understanding of the toxic effects of arsenic and warfare arsenicals on human health and environment

“…In this regard, miR-124 has been identified as a suppressor of ER stress-induced apoptosis (Panganiban et al, 2019 ), and a recent study demonstrated the neuroprotective role of miR-124 during arsenic-induced ER stress. Interestingly, genetic polymorphisms of miR-124 are associated with neurocognitive outcomes in children (Park et al, 2020 ). This study identifies miR-124 as a potential therapeutic target against arsenic-induced ER stress and neurotoxicity.…”

Proteomic Study on the Mechanism of Arsenic Neurotoxicity in the Rat Cerebral Cortex and the Protective Mechanism of Dictyophora Polysaccharides against Arsenic Neurotoxicity

“…As-induced apoptosis interrupted neurodevelopment in rats, leading to cognitive impairment . As exposure resulted in abnormal histological changes in mouse cerebral cortex tissue, neuronal degeneration, cytological changes, and cell shrinkage .…”

Cell Reprogramming With CRISPR/Cas9 Based Transcriptional Regulation Systems

“…miRNAs are coded by genes, so for their screening, the same rules as for protein-coding genes can be applied. For example, Panganiban et al (2019) uncovered multiple suppressors of endoplasmic reticulum stress via CRISPRn screening, among which was miRNA-124, and indeed in a further study miRNA-124 has shown to provide protection from arsenic-induced endoplasmic reticulum stress and a potential therapeutic target to counteract arsenic exposure ( Park et al, 2020 ).…”