Sunday, May 11, 2025
5/11/2025
Endoplasmic Reticulum Stress and Alcohol Neurotoxicity - Children who experience prenatal alcohol exposure may develop Fetal Alcohol Spectrum Disorders (FASD) and the central nervous system (CNS) is particularly susceptible to alcohol-induced damage. Children of FASD have significant neurobehavioral deficits. FASD is diagnosed at an alarmingly high rate making it the most common non-heritable cause of mental disability and resulting in tremendous personal and societal costs. It is therefore important to understand mechanisms that contribute to these adverse effects and find ways to improve outcomes in these individuals. The neurobehavioral deficits observed in FASD results from structural damages in the brain. It has been well-established that there is a temporal and spatial vulnerability to alcohol-induced neuronal damage during the development. That is, neurons at the different developmental stage display differential sensitivity to alcohol-induced damage. Even at the same developmental stage, neurons in different structures are differentially impacted by alcohol exposure. However, the underlying mechanisms are unclear. The endoplasmic reticulum (ER) is an important organelle involved in protein quality control. The accumulation of improperly folded proteins within the ER lumen results in ER stress, and sustained ER stress causes cell death. Neuronal cells are particularly sensitive to ER stress. Recently it is shown that ER stress plays an important and more specific role in alcohol-induced CNS damage. The ability of immature neurons to maintain ER homeostasis develops gradually and heterogeneously. We hypothesize that the temporal and spatial vulnerability of developing brain to alcohol-induced neuronal damage is mediated by the sensitivity to ER stress. That is, the differential sensitivity of neurons to alcohol neurotoxicity during the development is due to the difference of neuronal ability to maintain ER homeostasis and mitigate ER stress. We further hypothesize that enhancing neuronal ability to maintain ER homeostasis will make immature neurons resistant to alcohol-induced neurodegeneration and improve neurobehavioral deficits. We propose three specific aims to test these hypotheses. Specific Aim 1 will determine whether the temporal and spatial vulnerability to alcohol-induced neuronal damage is mediated by the sensitivity to ER stress in the developing brain. Specific Aim 2 will determine whether enhancing neuronal ability to maintain ER homeostasis can protect immature neurons against alcohol- induced ER stress and neurodegeneration in the developing brain. Specific Aim 3 will determine whether enhancing neuronal ability to maintain neuronal ER homeostasis can improve alcohol-induced neurobehavioral deficits. This proposal will use both in vitro and in vivo approaches to investigate how ER stress contributes to neuronal vulnerability to alcohol. It will employ genetic manipulations and chemical intervention by FDA-approved drugs to mitigate ER stress in immature neurons. The cohesive specific aims will not only elucidate the cellular and molecular mechanisms underlying the temporal and spatial vulnerability to alcohol, but also open a novel avenue for the intervention/therapy of FASD.
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