title: JNK-mediated activation of ATF2 contributes to dopaminergic neurodegeneration in the MPTP mouse model of Parkinson's disease.
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.
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China.
authors.forename: Qiaoying
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China.
authors.forename: Xin
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China.
authors.forename: Kunhua
authors.initials: K
authors.lastname: Hu
authors.affiliation: Cell Regulation Department, CRUK Manchester Institute, Wilmslow Road, Manchester M20 4BX, United Kingdom.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Breitwieser
authors.affiliation: 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.
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Mingtao
authors.initials: M
authors.lastname: Li
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D002452:Cell Count; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008636:Mesencephalon / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000209:etiology*; D020734:Parkinsonian Disorders / Q000150:complications* / Q000473:pathology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; D050483:Dopamine Plasma Membrane Transport Proteins; D014446:Tyrosine 3-Monooxygenase; D048670:MAP Kinase Kinase 4; D004298:Dopamine
keywords: ATF2; Dopaminergic neurodegeneration; JNK; Parkinson's disease