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Ethanol Activation of PKA Mediates Single-Minded 2 Expression in Neuronal Cells

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Abstract

Prenatal ethanol exposure can cause extensive apoptotic neurodegeneration throughout the developing central nervous system (CNS), which results in cognitive deficits and memory decline. However, the underlying mechanisms need further study. Single-minded 2 (Sim2), a transcriptional repressor, is reportedly involved in diseases that impair learning and memory, such as Down syndrome (DS) and Alzheimer’s disease. It is still unknown whether Sim2 is involved in regulating ethanol-mediated neuronal injury that might ultimately lead to neuronal dysfunction and subsequent learning and memory deficits. To study the effects of ethanol on Sim2 expression and neuronal injury, we used animal models and cell culture experiments. Our results indicated that in SH-SY5Y cells, ethanol exposure increased Sim2 expression and levels of cleaved caspase 3, which is a marker for cells undergoing apoptosis. Silencing Sim2 expression attenuated caspase 3 activation and cellular apoptosis. We also found that protein kinase A (PKA) activation induced Sim2 expression, as did ethanol. Inhibiting the PKA signaling pathway with H-89 decreased Sim2 expression and cleavage of caspase 3 that was induced by ethanol in vivo and in vitro. We further found that PKA regulated Sim2 expression at the transcriptional level. These results demonstrate that ethanol leads to increased Sim2 expression via the PKA pathway, ultimately resulting in apoptotic cell death.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (81170600), the Natural Science Foundation of Hubei Province (2012FFA038), and the Fundamental Research Funds for the Central Universities (2013QN176).

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The authors confirm there are no conflicts of interest.

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Authors and Affiliations

  1. Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Xiaolan Wang, Zhihua Yang, Yinan Sun, Hanjing Zhou, Guangpin Chu, Jing Zhang & Xianfang Meng

  2. The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, China

    Xiaolan Wang & Xianfang Meng

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  1. Xiaolan Wang
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  2. Zhihua Yang
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Correspondence to Xianfang Meng.

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Wang, X., Yang, Z., Sun, Y. et al. Ethanol Activation of PKA Mediates Single-Minded 2 Expression in Neuronal Cells. Mol Neurobiol 52, 1234–1244 (2015). https://doi.org/10.1007/s12035-014-8924-1

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  • DOI: https://doi.org/10.1007/s12035-014-8924-1

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