Autophagy and ethanol neurotoxicity

Jia Luo

doi:10.4161/15548627.2014.981916

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Journal article

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Peer reviewed

Autophagy and ethanol neurotoxicity

Jia Luo

Autophagy, Vol.10(12), pp.2099-2108

12/02/2014

DOI: 10.4161/15548627.2014.981916

PMCID: PMC4502825

PMID: 25484085

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Abstract

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.

AD, Alzheimer disease

alcohol

alcoholism

ALS, autophagy-lysosome system

AMPK, adenosine 5′-monophosphate-activated protein kinase

ATG, autophagy-related

CNS, central nervous system

development

ER, endoplasmic reticulum

FASD, fetal alcohol spectrum disorders

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

neurodegeneration

NFE2L2, nuclear factor, erythroid 2-like 2

NOX, NADPH oxidase

oxidative stress

PD, Parkinson disease

PI3K, class I phosphoinositide 3-kinase

protein degradation

ROS, reactive oxygen species

SQSTM1/p62, sequestosome 1

TSC1/2, tuberous sclerosis 1/ 2

UPR, unfolded protein response

Details

Title: Subtitle: Autophagy and ethanol neurotoxicity
Creators: Jia Luo - University of Kentucky
Resource Type: Journal article
Publication Details: Autophagy, Vol.10(12), pp.2099-2108
Publisher: Taylor & Francis
DOI: 10.4161/15548627.2014.981916
PMID: 25484085
PMCID: PMC4502825
ISSN: 1554-8627
eISSN: 1554-8635
Language: English
Date published: 12/02/2014
Academic Unit: Pathology
Record Identifier: 9984201250902771

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