Excessive ethanol exposure is detrimental to the brain. The developing brain is particularly vulnerable to ethanol such that prenatal ethanol exposure causes fetal alcohol spectrum disorders (FASD). Neuronal loss in the brain is the most devastating consequence and is associated with mental retardation and other behavioral deficits observed in FASD. Since alcohol consumption during pregnancy has not declined, it is imperative to elucidate the underlying mechanisms and develop effective therapeutic strategies. One cellular mechanism that acts as a protective response for the central nervous system (CNS) is autophagy. Autophagy regulates lysosomal turnover of organelles and proteins within cells, and is involved in cell differentiation, survival, metabolism, and immunity. We have recently shown that ethanol activates autophagy in the developing brain. The autophagic preconditioning alleviates ethanol-induced neuron apoptosis, whereas inhibition of autophagy potentiates ethanol-stimulated reactive oxygen species (ROS) and exacerbates ethanol-induced neuroapoptosis. The expression of genes encoding proteins required for autophagy in the CNS is developmentally regulated; their levels are much lower during an ethanol-sensitive period than during an ethanol-resistant period. Ethanol may stimulate autophagy through multiple mechanisms; these include induction of oxidative stress and endoplasmic reticulum stress, modulation of MTOR and AMPK signaling, alterations in BCL2 family proteins, and disruption of intracellular calcium (Ca2+) homeostasis. This review discusses the most recent evidence regarding the involvement of autophagy in ethanol-mediated neurotoxicity as well as the potential therapeutic approach of targeting autophagic pathways.
Keywords: AD, Alzheimer disease; ALS, autophagy-lysosome system; AMPK, adenosine 5′-monophosphate-activated protein kinase;; ATG, autophagy-related; CNS, central nervous system; ER, endoplasmic reticulum; FASD, fetal alcohol spectrum disorders; FOXO3, forkhead box O3; GSK3B, glycogen synthase kinase 3 β; HD, Huntington disease, HNSCs, hippocampal neural stem cells; LC3, microtubule-associated protein 1 light chain 3; MTOR, mechanistic target of rapamycin (serine/threonine kinase); MTORC1, MTOR complex 1; NFE2L2, nuclear factor, erythroid 2-like 2; NOX, NADPH oxidase; PD, Parkinson disease; PI3K, class I phosphoinositide 3-kinase; ROS, reactive oxygen species; SQSTM1/p62, sequestosome 1; TSC1/2, tuberous sclerosis 1/ 2; UPR, unfolded protein response; alcohol; alcoholism; development; fetal alcohol spectrum disorders; neurodegeneration; oxidative stress; protein degradation.