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    JNK-mediated activation of ATF2 contributes to dopaminergic neurodegeneration in the MPTP mouse model of Parkinson's disease.

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    Authors
    Huang, Q
    Du, X
    He, X
    Yu, Q
    Hu, K
    Breitwieser, Wolfgang
    Shen, Q
    Ma, S
    Li, M
    Affiliation
    Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2(nd) Road, Guangzhou 510080, China
    Issue Date
    2015-10-26
    
    Metadata
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    Abstract
    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.
    Citation
    JNK-mediated activation of ATF2 contributes to dopaminergic neurodegeneration in the MPTP mouse model of Parkinson's disease. 2015: Exp Neurol
    Journal
    Experimental Neurology
    URI
    http://hdl.handle.net/10541/592933
    DOI
    10.1016/j.expneurol.2015.10.010
    PubMed ID
    26515688
    Type
    Article
    Language
    en
    ISSN
    1090-2430
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.expneurol.2015.10.010
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