Expression of autophagy and UPR genes in the developing brain during ethanol-sensitive and resistant periods

Alexander Alimov; Haiping Wang; Mei Liu; Jacqueline A Frank; Mei Xu; Xiaoming Ou; Jia Luo

doi:10.1007/s11011-013-9430-2

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Expression of autophagy and UPR genes in the developing brain during ethanol-sensitive and resistant periods

Journal article

Peer reviewed

Expression of autophagy and UPR genes in the developing brain during ethanol-sensitive and resistant periods

Alexander Alimov, Haiping Wang, Mei Liu, Jacqueline A Frank, Mei Xu, Xiaoming Ou and Jia Luo

Metabolic brain disease, Vol.28(4), pp.667-676

12/2013

DOI: 10.1007/s11011-013-9430-2

PMCID: PMC3809151

PMID: 23979425

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Abstract

Fetal alcohol spectrum disorders (FASD) results from ethanol exposure to the developing fetus and is the leading cause of mental retardation. FASD is associated with a broad range of neurobehavioral deficits which may be mediated by ethanol-induced neurodegeneration in the developing brain. An immature brain is more susceptible to ethanol neurotoxicity. We hypothesize that the enhanced sensitivity of the immature brain to ethanol is due to a limited capacity to alleviate cellular stress. Using a third trimester equivalent mouse model of ethanol exposure, we demonstrated that subcutaneous injection of ethanol induced a wide-spread neuroapoptosis in postnatal day 4 (PD4) C57BL/6 mice, but had little effect on the brain of PD12 mice. We analyzed the expression profile of genes regulating apoptosis, and the pathways of ER stress response (also known as unfolded protein response, UPR) and autophagy during these ethanol-sensitive and resistant periods (PD4 versus PD12) using PCR microarray. The expression of pro-apoptotic genes, such as caspase-3, was much higher on PD4 than PD12; in contrast, the expression of genes that regulate UPR and autophagy, such as atf6, atg4, atg9, atg10, beclin1, bnip3, cebpb, ctsb, ctsd, ctss, grp78, ire1α, lamp, lc3 perk, pik3c3, and sqstm1 was significantly higher on PD12 than PD4. These results suggest that the vulnerability of the immature brain to ethanol could result from high expression of pro-apoptotic proteins and a deficiency in the stress responsive system, such as UPR and autophagy.

Animals

Autophagy - drug effects

Autophagy - genetics

Brain - drug effects

Brain - growth & development

Brain - metabolism

Caspase 3 - genetics

Caspase 3 - metabolism

Ethanol - pharmacology

Gene Expression Regulation, Developmental - drug effects

Mice

Mice, Inbred C57BL

Neurons - drug effects

Neurons - metabolism

Signal Transduction - drug effects

Unfolded Protein Response - drug effects

Unfolded Protein Response - genetics

Details

Title: Subtitle: Expression of autophagy and UPR genes in the developing brain during ethanol-sensitive and resistant periods
Creators: Alexander Alimov - University of Kentucky
Haiping Wang - University of Kentucky
Mei Liu - University of Kentucky
Jacqueline A Frank - University of Kentucky
Mei Xu - University of Kentucky
Xiaoming Ou - University of Mississippi Medical Center
Jia Luo - University of Kentucky
Resource Type: Journal article
Publication Details: Metabolic brain disease, Vol.28(4), pp.667-676
DOI: 10.1007/s11011-013-9430-2
PMID: 23979425
PMCID: PMC3809151
NLM abbreviation: Metab Brain Dis
ISSN: 0885-7490
eISSN: 1573-7365
Grant note: AA015407 / NIAAA NIH HHS R01 AA015407 / NIAAA NIH HHS R21 AA019693 / NIAAA NIH HHS AA019693 / NIAAA NIH HHS
Language: English
Date published: 12/2013
Academic Unit: Pathology
Record Identifier: 9984201252302771

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