Activation of transcription factor MEF2D by bis(3)-cognitin protects dopaminergic neurons and ameliorates Parkinsonian motor defects

Lu Yao, Wenming Li, Hua She, Juan Dou, Leili Jia, Yingli He, Qian Yang, Jinqiu Zhu, Natalie L. Cápiro, Douglas I. Walker, Kurt D. Pennell, Yuanping Pang, Yong Liu, Yifan Han, Zixu Mao

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Parkinson disease (PD) is characterized by the selective demise of dopaminergic (DA) neurons in the substantial nigra pars compacta. Dysregulation of transcriptional factor myocyte enhancer factor 2D (MEF2D) has been implicated in the pathogenic process in in vivo and in vitro models of PD. Here, we identified a small molecule bis(3)-cognitin (B3C) as a potent activator of MEF2D. We showed that B3C attenuated the toxic effects of neurotoxin 1-methyl-4-phenylpyridinium (MPP+) by activating MEF2D via multiple mechanisms. B3C significantly reduced MPP+-induced oxidative stress and potentiated Akt to down-regulate the activity of MEF2 inhibitor glycogen synthase kinase 3β (GSK3β) in a DA neuronal cell line SN4741. Furthermore, B3C effectively rescued MEF2D from MPP+-induced decline in both nucleic and mitochondrial compartments. B3C offered SN4741 cells potent protection against MPP+-induced apoptosis via MEF2D. Interestingly, B3C also protected SN4741 cells from wild type or mutant A53T α-synuclein-induced cytotoxicity. Using the in vivo PD model of C57BL/6 mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP), we showed that B3C maintained redox homeostasis, promoted Akt function activity, and restored MEF2D level in midbrain neurons. Moreover, B3C greatly prevented the loss of tyrosine hydroxylase signal in substantial nigra pars compacta DA neurons and ameliorated behavioral impairments in mice treated with MPTP. Collectedly, our studies identified B3C as a potent neuroprotective agent whose effectiveness relies on its ability to effectively up-regulate MEF2D in DA neurons against toxic stress in models of PD in vitro and in vivo.

Original languageEnglish (US)
Pages (from-to)34246-34255
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number41
DOIs
StatePublished - Oct 5 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Yao, L., Li, W., She, H., Dou, J., Jia, L., He, Y., Yang, Q., Zhu, J., Cápiro, N. L., Walker, D. I., Pennell, K. D., Pang, Y., Liu, Y., Han, Y., & Mao, Z. (2012). Activation of transcription factor MEF2D by bis(3)-cognitin protects dopaminergic neurons and ameliorates Parkinsonian motor defects. Journal of Biological Chemistry, 287(41), 34246-34255. https://doi.org/10.1074/jbc.M112.367540