MANF is neuroprotective against ethanol-induced neurodegeneration through ameliorating ER stress

Yongchao Wang; Wen Wen; Hui Li; Marco Clementino; Hong Xu; Mei Xu; Murong Ma; Jacqueline Frank; Jia Luo

doi:10.1016/j.nbd.2020.105216

Back

MANF is neuroprotective against ethanol-induced neurodegeneration through ameliorating ER stress

Journal article

Open access

Peer reviewed

MANF is neuroprotective against ethanol-induced neurodegeneration through ameliorating ER stress

Yongchao Wang, Wen Wen, Hui Li, Marco Clementino, Hong Xu, Mei Xu, Murong Ma, Jacqueline Frank and Jia Luo

Neurobiology of disease, Vol.148, pp.105216-105216

01/2021

DOI: 10.1016/j.nbd.2020.105216

PMID: 33296727

Files and links (1)

url

https://doi.org/10.1016/j.nbd.2020.105216View

Published (Version of record) Open Access

Abstract

Fetal alcohol spectrum disorders (FASD) are a spectrum of developmental disorders caused by prenatal alcohol exposure. Neuronal loss or neurodegeneration in the central nervous system (CNS) is one of the most devastating features in FASD. It is imperative to delineate the underlying mechanisms to facilitate the treatment of FASD. Endoplasmic reticulum (ER) stress is a hallmark and an underlying mechanism of many neurodegenerative diseases, including ethanol-induced neurodegeneration. Mesencephalic astrocyte-derived neurotrophic factor (MANF) responds to ER stress and has been identified as a protein upregulated in response to ethanol exposure during the brain development. To investigate the role of MANF in ethanol-induced neurodegeneration and its association with ER stress regulation, we established a CNS-specific Manf knockout mouse model and examined the effects of MANF deficiency on ethanol-induced neuronal apoptosis and ER stress using a third-trimester equivalent mouse model. We found MANF deficiency exacerbated ethanol-induced neuronal apoptosis and ER stress and that blocking ER stress abrogated the harmful effects of MANF deficiency on ethanol-induced neuronal apoptosis. Moreover, using an animal model of ER-stress-induced neurodegeneration, we demonstrated that MANF deficiency potentiated tunicamycin (TM)-induced ER stress and neurodegeneration. A whole transcriptome RNA sequencing also supported the functionality of MANF in ER stress modulation and revealed targets that may mediate the ER stress-buffering capacity of MANF. Collectively, these results suggest that MANF is a neurotrophic factor that can protect neurons against ethanol-induced neurodegeneration by ameliorating ER stress. •Conditional MANF knockout in the CNS alters endoplasmic reticulum (ER)-related RNA signature in the developing mouse brain.•The ablation of MANF in CNS exacerbates EtOH- and tunicamycin (TM)-induced ER stress and neuronal apoptosis.•ER stress plays an important role in MANF deficiency-promoted neuronal apoptosis in EtOH- and TM-exposed developing brain.

Alcohol abuse

Apoptosis

Brain

Development

Unfolded protein response

Details

Title: Subtitle: MANF is neuroprotective against ethanol-induced neurodegeneration through ameliorating ER stress
Creators: Yongchao Wang - Vanderbilt University
Wen Wen - University of Iowa
Hui Li - University of Iowa
Marco Clementino - University of Kentucky
Hong Xu - University of Kentucky
Mei Xu - University of Kentucky
Murong Ma - University of Kentucky
Jacqueline Frank - University of Kentucky
Jia Luo - University of Iowa
Resource Type: Journal article
Publication Details: Neurobiology of disease, Vol.148, pp.105216-105216
DOI: 10.1016/j.nbd.2020.105216
PMID: 33296727
NLM abbreviation: Neurobiol Dis
ISSN: 0969-9961
eISSN: 1095-953X
Publisher: Elsevier Inc
Grant note: DOI: 10.13039/100000738, name: U.S. Department of Veterans Affairs; DOI: 10.13039/100000027, name: National Institute on Alcohol Abuse and Alcoholism
Language: English
Date published: 01/2021
Academic Unit: Pathology
Record Identifier: 9984186574802771

Metrics

7 Record Views

37 Times Cited - Web of Science