Journal article
Alcohol Disrupts Neural Differentiation Through Endoplasmic Reticulum Stress and PERK Pathway Activation
Neurochemistry international, Vol.192, 106108
12/29/2025
DOI: 10.1016/j.neuint.2025.106108
PMID: 41475444
Abstract
Prenatal alcohol exposure (PAE) can lead to fetal alcohol spectrum disorder (FASD), a condition marked by developmental brain defects that result in neurobehavioral and cognitive impairments. However, the underlying molecular mechanisms remain poorly understood. Brain development is a highly regulated process, with neurogenesis playing a crucial role. A key stage in this process is neural differentiation, which is essential for proper brain function. This study aims to investigate how alcohol disrupts neural differentiation. NE-4C cells, a neural stem cell line derived from the mouse embryonic brain, were utilized as an in vitro model. As an in vivo model, pregnant mice were exposed to alcohol between gestation days 14 and 16, after which newly formed neurons in the ventricular zone (VZ) were analyzed. To examine the role of endoplasmic reticulum (ER) stress, tunicamycin (TM), and MANF-deficient NE-4C cells were employed. Neural differentiation was assessed using immunofluorescence, immunoblotting and flow cytometry. Alcohol impaired the differentiation of NE-4C cells into neurons and astrocytes without impacting cell migration. It also induced ER stress, preferably activating the PERK pathway. Similarly, ER stress caused by TM and MANF deficiency disrupted neural differentiation and activated PERK. Inhibiting PERK mitigated alcohol-induced impairment of neuronal differentiation. PAE decreased the number of newly formed neurons in the VZ of fetal brain while having little effects on cell survival and proliferation. Inhibiting PERK partially reversed the reduction of new neurons caused by PAE. Thus, alcohol-induced ER stress, particularly PERK activation, may contribute to impaired neurogenesis linked to FASD.
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•Alcohol impairs neural differentiation of NE-4C cells into neurons and astrocytes.•Prenatal alcohol exposure reduces the number of newly formed neurons in the ventricular zone of fetal mouse brains.•Alcohol induces endoplasmic reticulum (ER) stress, specifically activating the PERK signaling pathway.•Inhibition of PERK partially restores neuronal differentiation in both in vitro and in vivo models.•PERK-mediated ER stress is a key mechanism underlying alcohol-induced neurogenesis defects in fetal alcohol spectrum disorder.
Details
- Title: Subtitle
- Alcohol Disrupts Neural Differentiation Through Endoplasmic Reticulum Stress and PERK Pathway Activation
- Creators
- Zuohui Zhang - University of IowaWen Wen - University of IowaHong Lin - University of IowaDi Hu - University of IowaHui Li - University of IowaJia Luo - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- Neurochemistry international, Vol.192, 106108
- DOI
- 10.1016/j.neuint.2025.106108
- PMID
- 41475444
- NLM abbreviation
- Neurochem Int
- ISSN
- 0197-0186
- eISSN
- 1872-9754
- Publisher
- Elsevier Ltd
- Grant note
- National Institutes of Health (NIH): AA017226, AA015407
This work was supported by the National Institutes of Health (NIH) grants AA017226 and AA015407. We thank Jianyu Yu for his assistance in the experiment of flow cytometry analysis.
- Language
- English
- Date published
- 12/29/2025
- Academic Unit
- Stead Family Department of Pediatrics; Pathology; Neuroscience and Pharmacology
- Record Identifier
- 9985113256402771
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