Activation of Transcription Factor MEF2D by Bis(3)-cognitin Protects Dopaminergic Neurons and Ameliorates Parkinsonian Motor Defects

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

doi:10.1074/jbc.m112.367540

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.

Highlights

Dysregulation of myocyte enhancer factor 2D (MEF2D) is implicated in the pathogenic process of Parkinson disease (PD)
Our analysis showed that MPPϩ treatment reduces Akt activity and the inhibitory phosphorylation of GSK3␤ at Ser-9 (Fig. 2C)
Mitochondrial dysfunction, apoptosis, autophagy, and proteasome dysfunction have all been proposed as new therapeutic approaches for PD [10]

Summary

Background

Dysregulation of myocyte enhancer factor 2D (MEF2D) is implicated in the pathogenic process of Parkinson disease (PD). B3C significantly reduced MPP؉-induced oxidative stress and potentiated Akt to down-regulate the activity of MEF2 inhibitor glycogen synthase kinase 3␤ (GSK3␤) in a DA neuronal cell line SN4741. Many genetic and neurotoxic insults associated with PD reduce mitochondrial activity and increase oxidative level, which lead to dysregulation of key downstream pathways including PI3K/Akt-GSK3␤ (4 –7). Despite this progress, therapeutically, most of the medications currently available for PD offer only symptomatic benefits without a disease-modifying potential [8, 9]. Efforts over the last decade have failed to establish neuroprotective interventions as true therapeutics able to effectively slow the progression of PD because no genuine new therapeutic targets key to

A Small MEF2D Activator

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION