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Nuclear Accumulation of Histone Deacetylase 4 (HDAC4) Exerts Neurotoxicity in Models of Parkinson’s Disease

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Abstract

Histone deacetylase 4 (HDAC4) is a class II HDAC which is highly expressed in the brain. Previous reports have shown that HDAC4 is essential for normal brain physiology and its deregulation leads to several neurodegenerative disorders. However, it remains unclear whether dysregulation of HDAC4 is specifically involved in the development of Parkinson’s disease. In this study, we demonstrate that intracellular trafficking of HDAC4 is important in regulating dopaminergic cell death. While HDAC4 normally localizes to the cytoplasm, nuclear accumulation of HDAC4 was observed in dopaminergic neurons overexpressing A53T mutant α-synuclein treated with MPP+/MPTP in vitro and in vivo. Nuclear-localized HDAC4 repressed cAMP response element-binding protein (CREB) and myocyte enhancer factor 2A (MEF2A), altered neuronal gene expression, and promoted neuronal apoptosis. Furthermore, cytoplasm-to-nucleus shuttling of HDAC4 was determined by its phosphorylation status, which was regulated by PP2A and PKCε. Treatment with PKCε-specific activators, DCP-LA or Bryostatin 1, provided neuroprotection against MPP+ toxicity in a dose-dependent manner. In summary, our research illustrated that intracellular trafficking of HDAC4 contributes to the vulnerability of cells expressing pathogenic α-synuclein mutants in response to oxidative stress and compounds which maintain cytoplasmic localization of HDAC4 such as PKCε activators that may serve as therapeutic agents for Parkinson’s disease.

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Acknowledgments

We would like to acknowledge that the pcDNA-HDAC4.3SA-FLAG was a gift from Tso-Pang Yao. This work was supported by grants from “Key New Drug Creation and Manufacturing Program” of the National Science & Technology Major Project (2014ZX09102-001-05) and the Scientific Innovation Project of the Chinese Academy of Sciences (XDA12040304). All experiments were conducted in compliance with the ARRIVE guidelines.

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  1. CAS Key Laboratory of Receptor Research, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, 555 Zu Chong Zhi Road, Shanghai, 201203, People’s Republic of China

    Qimei Wu, Xiaoyu Yang, Lei Zhang, Yu Zhang & Linyin Feng

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  1. Qimei Wu
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Wu, Q., Yang, X., Zhang, L. et al. Nuclear Accumulation of Histone Deacetylase 4 (HDAC4) Exerts Neurotoxicity in Models of Parkinson’s Disease. Mol Neurobiol 54, 6970–6983 (2017). https://doi.org/10.1007/s12035-016-0199-2

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