Destabilization of survival factor MEF2D mRNA by neurotoxin in models of Parkinson's disease

Authors

  • Bao Wang,

    1. Department of Neurosurgery, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China
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    • These authors contributed equally to this work.
  • Zhibiao Cai,

    1. Department of Neurosurgery, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China
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    • These authors contributed equally to this work.
  • Fangfang Lu,

    1. Department of Neurosurgery, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China
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  • Chen Li,

    1. Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, Ningxia, China
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  • Xiaofei Zhu,

    1. Department of Neurology, KunMing General Hospital of The People's Liberation Army, Kunming, Yunnan, China
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  • Linna Su,

    1. State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital of Digestive Diseases, Xi'an, Shaanxi, China
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  • Guodong Gao,

    Corresponding author
    1. Department of Neurosurgery, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China
    • Address correspondence and reprint requests to Qian Yang and Guodong Gao, Department of Neurosurgery, Tangdu Hospital, the Fourth Military Medical University, 569 Xinsi Road, Xi'an, Shannxi, 710038 China. E-mails: qianyang@fmmu.edu.cn and gguodong@fmmu.edu.cn

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  • Qian Yang

    Corresponding author
    1. Department of Neurosurgery, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China
    • Address correspondence and reprint requests to Qian Yang and Guodong Gao, Department of Neurosurgery, Tangdu Hospital, the Fourth Military Medical University, 569 Xinsi Road, Xi'an, Shannxi, 710038 China. E-mails: qianyang@fmmu.edu.cn and gguodong@fmmu.edu.cn

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Abstract

Progressive loss of dopaminergic (DA) neurons in the substantial nigra pars compacta (SNc) is an important pathological feature in Parkinson's disease (PD). Loss of transcription factor myocyte enhancer factor 2D (MEF2D), a key neuronal survival factor, has been shown to underlie the loss of DA neurons in SNc and the pathogenic process of PD. It is known that PD-associated neurotoxins reduce the level of MEF2D protein to trigger neuronal death. Although neurotoxins clearly destabilize MEF2D by post-translational mechanisms, it is not known whether regulation of MEF2D mRNA contributes to neurotoxin-induced decrease in MEF2D protein. In this work, we showed that MPP+, the toxic metabolite of MPTP, caused a significant decrease in the half-life and total level of MEF2D mRNA in a DA neuronal cell line, SN4741 cells. Quantitative PCR analysis of the SNc DA neurons captured by immune-laser capture microdissection showed that exposure to MPTP led to a marked reduction in the level of MEF2D mRNA in SNc DA neurons compared to controls. Down-regulation of MEF2D mRNA alone reduced the viability of SN4741 cells and sensitized the cells to MPP+-induced toxicity. These results suggest that destabilization and reduction in MEF2D mRNA is in part responsible for neurotoxin-induced decrease in MEF2D protein and neuronal viability.

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Myocyte enhancer factor 2D (MEF2D) plays an important role in neuronal survival. How MEF2D mRNA is deregulated under toxic stress is unclear. We found that PD-associated neurotoxins destabilize MEF2D mRNA and reduce its level in vitro and in vivo. Reduction in MEF2D mRNA is sufficient to sensitize model cells to neurotoxin-induced toxicity, suggesting that destabilization of MEF2D mRNA is part of the mechanism by which neurotoxins trigger deregulation of neuronal survival.

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