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      Nuclear receptor Nurr1 agonists enhance its dual functions and improve behavioral deficits in an animal model of Parkinson’s disease

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      Author
      Kim, Chun-Hyung
      Han, Baek-Soo
      Moon, Jisook
      Kim, Deog-Joong
      Shin, Joon
      Rajan, Sreekanth
      Nguyen, Quoc Toan
      Sohn, Mijin
      Kim, Won-Gon
      Han, Minjoon
      Jeong, Inhye
      Kim, Kyoung-Shim
      Lee, Eun-Hye
      Tu, Yupeng
      Naffin-Olivos, Jacqueline L.
      Park, Chang-Hwan
      Ringe, Dagmar
      Yoon, Ho Sup
      Petsko, Gregory A.
      Kim, Kwang-Soo
      Date of Issue
      2015
      School
      School of Biological Sciences
      Abstract
      Parkinson’s disease (PD), primarily caused by selective degeneration of midbrain dopamine (mDA) neurons, is the most prevalent movement disorder, affecting 1–2% of the global population over the age of 65. Currently available pharmacological treatments are largely symptomatic and lose their efficacy over time with accompanying severe side effects such as dyskinesia. Thus, there is an unmet clinical need to develop mechanism-based and/or disease-modifying treatments. Based on the unique dual role of the nuclear orphan receptor Nurr1 for development and maintenance of mDA neurons and their protection from inflammation-induced death, we hypothesize that Nurr1 can be a molecular target for neuroprotective therapeutic development for PD. Here we show successful identification of Nurr1 agonists sharing an identical chemical scaffold, 4-amino-7-chloroquinoline, suggesting a critical structure–activity relationship. In particular, we found that two antimalarial drugs, amodiaquine and chloroquine stimulate the transcriptional function of Nurr1 through physical interaction with its ligand binding domain (LBD). Remarkably, these compounds were able to enhance the contrasting dual functions of Nurr1 by further increasing transcriptional activation of mDA-specific genes and further enhancing transrepression of neurotoxic proinflammatory gene expression in microglia. Importantly, these compounds significantly improved behavioral deficits in 6-hydroxydopamine lesioned rat model of PD without any detectable signs of dyskinesia-like behavior. These findings offer proof of principle that small molecules targeting the Nurr1 LBD can be used as a mechanism-based and neuroprotective strategy for PD.
      Subject
      NR4A2
      Nurr1
      Parkinson’s disease
      Agonist
      Drug target
      Type
      Journal Article
      Series/Journal Title
      Proceedings of the National Academy of Sciences of the United States of America
      Rights
      © 2015 The Authors (Published by National Academy of Sciences).
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      • SBS Journal Articles
      http://dx.doi.org/10.1073/pnas.1509742112
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