Activation of transcription factor MEF2D by bis(3)-cognitin protects dopaminergic neurons and ameliorates Parkinsonian motor defects.
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.
Institute of Neurobiology, Environment and Genes Related to Diseases, Key Laboratory of Education Ministry, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, China.
Lu
L
Yao
Wenming
W
Li
Hua
H
She
Juan
J
Dou
Leili
L
Jia
Yingli
Y
He
Qian
Q
Yang
Jinqiu
J
Zhu
Natalie L
NL
Cápiro
Douglas I
DI
Walker
Kurt D
KD
Pennell
Yuanping
Y
Pang
Yong
Y
Liu
Yifan
Y
Han
Zixu
Z
Mao
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D002460:Cell Line; D015259:Dopamine Agents / Q000009:adverse effects / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D006540:Herbicides / Q000009:adverse effects / Q000494:pharmacology; D064326:MEF2 Transcription Factors; D008297:Male; D051379:Mice; D018006:Myogenic Regulatory Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D013619:Tacrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D015259:Dopamine Agents; D006540:Herbicides; D064326:MEF2 Transcription Factors; C578044:Mef2d protein, mouse; D018006:Myogenic Regulatory Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C577051:bis(3)-cognitin; D013619:Tacrine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D015655:1-Methyl-4-phenylpyridinium