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DJ-1/PARK7, But Not Its L166P Mutant Linked to Autosomal Recessive Parkinsonism, Modulates the Transcriptional Activity of the Orphan Nuclear Receptor Nurr1 In Vitro and In Vivo

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Abstract

Although mutations of DJ-1 have been linked to autosomal recessive Parkinsonism for years, its physiological function and the pathological mechanism of its mutants are not well understood. We report for the first time that exogenous application of DJ-1, but not its L166P mutant, enhances the nuclear translocation and the transcriptional activity of Nurr1, a transcription factor essential for dopaminergic neuron development and maturation, both in vitro and in vivo. Knockdown of DJ-1 attenuates Nurr1 activity. Further investigation showed that signaling of Raf/MEK/ERK MAPKs is involved in this regulatory process and that activation induced by exogenous DJ-1 is antagonized by U0126, an ERK pathway inhibitor, indicating that DJ-1 modulates Nurr1 activity via the Raf/MEK/ERK pathway. Our findings shed light on the novel function of DJ-1 to enhance Nurr1 activity and provide the first insight into the molecular mechanism by which DJ-1 enhances Nurr1 activity.

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Acknowledgments

We thank Dr. Yaohua Li for kindly providing us with the plasmids of phRLTK, pGL3-basic, pGL3-THprom, and pGL3-control. This work was supported by grants from the National Basic Research Program of China (2011CB504102 and 2012CB722407), the National Natural Science Foundation of China (81200995, 81371398, and 30950003), the Importation and Development of High-Caliber Talents Project of Beijing Municipal Institutions (CIT and TCD 201404179), the Natural Science Foundation of Beijing (7131001), the Project of Construction of Innovative Teams and Teacher Career Development for Universities and Colleges Under Beijing Municipality (IDHT20140514), and BIBD-PXM2013_014226_07_000084.

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  1. Center of Parkinson’s Disease, Beijing Institute for Brain Disorders, Department of Neurobiology, Capital Medical University, Beijing Center of Neural Regeneration and Repair, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Beijing, 100069, China

    Lingling Lu, Shasha Zhao, Ge Gao, Xiaohong Sun, Huanying Zhao & Hui Yang

  2. Center of Parkinson’s Disease, Beijing Institute of Brain Disorders, Capital Medical University, Beijing Center of Neural Regeneration and Repair, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, 10 You an men Wai, Xitoutiao, Beijing, 100069, China

    Hui Yang

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  1. Lingling Lu
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Correspondence to Hui Yang.

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Supplementary Fig. 1

Western blot analysis of pP38 and pJNK protein level in MN9D cells overexpressing WT DJ-1 or mutant L166P. Representative western blots (lower panels) and quantitative analysis (upper panels) for pP38 (a) and pJNK (b). Overexpression of the WT DJ-1 or mutant L166P constructs did not significantly alter phosphorylation of P38 or JNK. (JPG 37 kb)

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Lu, L., Zhao, S., Gao, G. et al. DJ-1/PARK7, But Not Its L166P Mutant Linked to Autosomal Recessive Parkinsonism, Modulates the Transcriptional Activity of the Orphan Nuclear Receptor Nurr1 In Vitro and In Vivo. Mol Neurobiol 53, 7363–7374 (2016). https://doi.org/10.1007/s12035-016-9772-y

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