Journal article
Upregulation of mesencephalic astrocyte-derived neurotrophic factor (MANF) expression offers protection against alcohol neurotoxicity
Journal of neurochemistry, Vol.166(6), pp.943-959
09/2023
DOI: 10.1111/jnc.15921
PMCID: PMC10906989
PMID: 37507360
Appears in UI Libraries Support Open Access
Abstract
Alcohol exposure has detrimental effects on both the developing and mature brain. Endoplasmic reticulum (ER) stress is one of the mechanisms that contributes to alcohol-induced neuronal damages. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress-responsive protein and is neuroprotective in multiple neuronal injury and neurodegenerative disease models. MANF deficiency has been shown to exacerbate alcohol-induced ER stress and neurodegeneration. However, it is unknown whether MANF supplement is sufficient to protect against alcohol neurotoxicity. Alcohol alters MANF expression in the brain, but the mechanisms underlying alcohol modulation of MANF expression remain unclear. This study was designed to determine how alcohol alters MANF expression in neuronal cells and whether exogeneous MANF can alleviate alcohol neurotoxicity. We showed that alcohol increased MANF transcription and secretion without affecting MANF mRNA stability and protein degradation. ER stress was necessary for alcohol-induced MANF upregulation, as pharmacological inhibition of ER stress by 4-PBA diminished alcohol-induced MANF expression. In addition, the presence of ER stress response element II (ERSE-II) was required for alcohol-stimulated MANF transcription. Mutations or deletion of this sequence abolished alcohol-regulated transcriptional activity. We generated MANF knockout (KO) neuronal cells using CRISPR/Cas9. MANF KO cells exhibited increased unfolded protein response (UPR) and were more susceptible to alcohol-induced cell death. On the other hand, MANF upregulation by the addition of recombinant MANF protein or adenovirus gene transduction protected neuronal cells against alcohol-induced cell death. Further studies using early postnatal mouse pups demonstrated that enhanced MANF expression in the brain by intracerebroventricular (ICV) injection of MANF adeno-associated viruses ameliorated alcohol-induced cell death. Thus, alcohol increased MANF expression through inducing ER stress, which could be a protective response. Exogenous MANF was able to protect against alcohol-induced neurodegeneration.
Details
- Title: Subtitle
- Upregulation of mesencephalic astrocyte-derived neurotrophic factor (MANF) expression offers protection against alcohol neurotoxicity
- Creators
- Wen Wen - University of IowaYongchao Wang - Vanderbilt University Medical CenterHui Li - University of IowaDi Hu - University of IowaHong Lin - University of IowaZuohui Zhang - University of IowaJia Luo - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Journal of neurochemistry, Vol.166(6), pp.943-959
- DOI
- 10.1111/jnc.15921
- PMID
- 37507360
- PMCID
- PMC10906989
- NLM abbreviation
- J Neurochem
- eISSN
- 1471-4159
- Publisher
- Wiley
- Grant note
- DOI: 10.13039/100007496, name: Biomedical Laboratory Research and Development, VA Office of Research and Development, award: BX001721; DOI: 10.13039/100000027, name: National Institute on Alcohol Abuse and Alcoholism, award: AA015407, AA017226
- Language
- English
- Electronic publication date
- 07/28/2023
- Date published
- 09/2023
- Academic Unit
- Pathology
- Record Identifier
- 9984447954802771
Metrics
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