Endoplasmic Reticulum Stress and Ethanol Neurotoxicity

Abstract

Ethanol abuse affects virtually all organ systems and the central nervous system (CNS) is particularly vulnerable to excessive ethanol exposure. Ethanol exposure causes profound damages to both the adult and developing brain. Prenatal ethanol exposure induces fetal alcohol spectrum disorders (FASD) which is associated with mental retardation and other behavioral deficits. A number of potential mechanisms have been proposed for ethanol-induced brain damage; these include the promotion of neuroinflammation, interference with signaling by neurotrophic factors, induction of oxidative stress, modulation of retinoid acid signaling, and thiamine deficiency. The endoplasmic reticulum (ER) regulates posttranslational protein processing and transport. The accumulation of unfolded or misfolded proteins in the ER lumen triggers ER stress and induces unfolded protein response (UPR) which are mediated by three transmembrane ER signaling proteins: pancreatic endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). UPR is initiated to protect cells from overwhelming ER protein loading. However, sustained ER stress may result in cell death. ER stress has been implied in various CNS injuries, including brain ischemia, traumatic brain injury, and aging-associated neurodegeneration, such as Alzheimer’s disease (AD), Huntington’s disease (HD), Amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD). However, effects of ethanol on ER stress in the CNS receive less attention. In this review, we discuss recent progress in the study of ER stress in ethanol-induced neurotoxicity. We also examine the potential mechanisms underlying ethanol-mediated ER stress and the interaction among ER stress, oxidative stress and autophagy in the context of ethanol neurotoxicity.

Thiamine deficiency induces endoplasmic reticulum stress and oxidative stress in human neurons derived from induced pluripotent stem cells

“…However, when UPR is insufficient to restore ER homeostasis, apoptosis occurs (Morishima et al, 2004; Tabas and Ron, 2011). During the UPR, three major UPR sensors, namely PERK (protein kinase RNA-like ER kinase), IRE1 (inositol requiring protein-1), and ATF6 (activating transcription factor-6), are activated to restore folding capacity (Hetz et al, 2011; Yang and Luo, 2015). Neurodegenerative diseases, such as AD, PD, and HD, have in common the presence of protein aggregates in specific brain areas where significant neuronal loss is detected.…”

Nonhazardous Solvent Systems for Processing Perovskite Photovoltaics

“…The most common of the alcohols, EtOH, exhibits noticeably adverse health effects only from chronic oral ingestion generally due to substance abuse. [ 25 ] A higher alcohol with a longer carbon chain, PrOH, is categorized as a slight irritant and has no known liver toxicity to humans. [ 26 ] In regards to chronic substance abuse, GBL is similar to EtOH.…”

Thiamine Deficiency and Neurodegeneration: the Interplay Among Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy

“…Therefore, UPR is generally considered a cellular defense mechanism. During the UPR, three major UPR sensors, namely PERK (protein kinase RNA-like ER kinase), IRE1 (inositol requiring protein-1), and ATF6 (activating transcription factor-6), transduce information about the folding status of the ER to the cytosol and nucleus to restore folding capacity [91, 92]. …”