Affiliation:
1. Department of Pathology University of Iowa Carver College of Medicine Iowa City Iowa USA
2. Vanderbilt Memory and Alzheimer's Center Department of Neurology Vanderbilt University Medical Center Nashville Tennessee USA
3. VA Iowa City Health Care System Iowa City Iowa USA
Abstract
AbstractAlcohol 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.image
Funder
Biomedical Laboratory Research and Development, VA Office of Research and Development
National Institute on Alcohol Abuse and Alcoholism
Subject
Cellular and Molecular Neuroscience,Biochemistry
Cited by
1 articles.
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