PMID- 26515688
OWN - NLM
STAT- MEDLINE
DCOM- 20160627
LR  - 20170918
IS  - 1090-2430 (Electronic)
IS  - 0014-4886 (Linking)
VI  - 277
DP  - 2016 Mar
TI  - JNK-mediated activation of ATF2 contributes to dopaminergic neurodegeneration in 
      the MPTP mouse model of Parkinson's disease.
PG  - 296-304
LID - S0014-4886(15)30111-4 [pii]
LID - 10.1016/j.expneurol.2015.10.010 [doi]
AB  - The c-Jun N-terminal kinase (JNK)/c-Jun pathway is a known critical regulator of 
      dopaminergic neuronal death in Parkinson's disease (PD) and is considered a 
      potential target for neuroprotective therapy. However, whether JNK is activated 
      within dopaminergic neurons remains controversial, and whether JNK acts through 
      downstream effectors other than c-Jun to promote dopaminergic neuronal death 
      remains unclear. In this study, we confirm that JNK but not p38 is activated in 
      dopaminergic neurons after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 
      (MPTP)-intoxication. Furthermore, within the dopaminergic neurons of the 
      substantia nigra in MPTP-treated mice, JNK2/3 phosphorylates threonine 69 (Thr69) 
      of Activating transcription factor-2 (ATF2), a transcription factor of the 
      ATF/CREB family, whereas the phosphorylation of Thr71 is constitutive and remains 
      unchanged. The increased phosphorylation of ATF2 on Thr69 by JNK in the MPTP 
      mouse model suggests a functional relationship between the transcriptional 
      activation of ATF2 and dopaminergic neuron death. By using dopaminergic 
      neuron-specific conditional ATF2 mutant mice, we found that either partial or 
      complete deletion of the ATF2 DNA-binding domain in dopaminergic neurons markedly 
      alleviates the MPTP-induced dopaminergic neurodegeneration, indicating that the 
      activation of ATF2 plays a detrimental role in neuropathogenesis in PD. Taken 
      together, our findings demonstrate that JNK-mediated ATF2 activation contributes 
      to dopaminergic neuronal death in an MPTP model of PD.
CI  - Copyright (c) 2015 Elsevier Inc. All rights reserved.
FAU - Huang, Qiaoying
AU  - Huang Q
AD  - Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 
      74 Zhongshan 2nd Road, Guangzhou 510080, China.
FAU - Du, Xiaoxiao
AU  - Du X
AD  - Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 
      74 Zhongshan 2nd Road, Guangzhou 510080, China.
FAU - He, Xin
AU  - He X
AD  - Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 
      74 Zhongshan 2nd Road, Guangzhou 510080, China.
FAU - Yu, Qing
AU  - Yu Q
AD  - Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 
      74 Zhongshan 2nd Road, Guangzhou 510080, China.
FAU - Hu, Kunhua
AU  - Hu K
AD  - Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 
      74 Zhongshan 2nd Road, Guangzhou 510080, China.
FAU - Breitwieser, Wolfgang
AU  - Breitwieser W
AD  - Cell Regulation Department, CRUK Manchester Institute, Wilmslow Road, Manchester 
      M20 4BX, United Kingdom.
FAU - Shen, Qingyu
AU  - Shen Q
AD  - Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School 
      of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, 
      China; Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen 
      University, Number 107, Yan Jiang Xi Road, Guangzhou 510120, China.
FAU - Ma, Shanshan
AU  - Ma S
AD  - Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 
      74 Zhongshan 2nd Road, Guangzhou 510080, China. Electronic address: 
      mashsh3@mail.sysu.edu.cn.
FAU - Li, Mingtao
AU  - Li M
AD  - Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 
      74 Zhongshan 2nd Road, Guangzhou 510080, China; Guangdong Province Key Laboratory 
      of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen 
      University, 74 Zhongshan 2nd Road, Guangzhou 510080, China. Electronic address: 
      limt@mail.sysu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151026
PL  - United States
TA  - Exp Neurol
JT  - Experimental neurology
JID - 0370712
RN  - 0 (Activating Transcription Factor 2)
RN  - 0 (Atf2 protein, mouse)
RN  - 0 (Dopamine Plasma Membrane Transport Proteins)
RN  - EC 1.14.16.2 (Tyrosine 3-Monooxygenase)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 4)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Activating Transcription Factor 2/genetics/*metabolism
MH  - Analysis of Variance
MH  - Animals
MH  - Cell Count
MH  - Disease Models, Animal
MH  - Dopamine/*metabolism
MH  - Dopamine Plasma Membrane Transport Proteins/genetics/metabolism
MH  - Gene Expression Regulation/drug effects/*genetics
MH  - MAP Kinase Kinase 4/genetics/*metabolism
MH  - Male
MH  - Mesencephalon/metabolism/pathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Mutation/genetics
MH  - Neurodegenerative Diseases/*etiology
MH  - Parkinsonian Disorders/*complications/pathology
MH  - Time Factors
MH  - Tyrosine 3-Monooxygenase/metabolism
OTO - NOTNLM
OT  - ATF2
OT  - Dopaminergic neurodegeneration
OT  - JNK
OT  - Parkinson's disease
EDAT- 2015/10/31 06:00
MHDA- 2016/06/28 06:00
CRDT- 2015/10/31 06:00
PHST- 2015/04/18 00:00 [received]
PHST- 2015/10/02 00:00 [revised]
PHST- 2015/10/24 00:00 [accepted]
PHST- 2015/10/31 06:00 [entrez]
PHST- 2015/10/31 06:00 [pubmed]
PHST- 2016/06/28 06:00 [medline]
AID - S0014-4886(15)30111-4 [pii]
AID - 10.1016/j.expneurol.2015.10.010 [doi]
PST - ppublish
SO  - Exp Neurol. 2016 Mar;277:296-304. doi: 10.1016/j.expneurol.2015.10.010. Epub 2015 
      Oct 26.