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Proc Natl Acad Sci U S A. 2015 Jul 14;112(28):8756-61. doi: 10.1073/pnas.1509742112. Epub 2015 Jun 29.

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

Author information

1
Molecular Neurobiology Lab, McLean Hospital and Program in Neuroscience, Harvard Medical School, Belmont, MA 02478; Institute of Green Bio Science and Technology, Seoul National University, Kangwon-Do, Korea; kskim@mclean.harvard.edu chkim@mclean.harvard.edu gpetsko@med.cornell.edu.
2
Molecular Neurobiology Lab, McLean Hospital and Program in Neuroscience, Harvard Medical School, Belmont, MA 02478; Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea;
3
Molecular Neurobiology Lab, McLean Hospital and Program in Neuroscience, Harvard Medical School, Belmont, MA 02478; Department of Biotechnology, College of Life Science, CHA University, Seoul, Korea;
4
Molecular Neurobiology Lab, McLean Hospital and Program in Neuroscience, Harvard Medical School, Belmont, MA 02478;
5
School of Biological Sciences, Nanyang Technological University, Singapore;
6
Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea;
7
Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea;
8
Departments of Biochemistry and Chemistry, Brandeis University, Waltham, MA 02453;
9
School of Biological Sciences, Nanyang Technological University, Singapore; Department of Genetic Engineering, College of Life Sciences, Kyung Hee University, Seoul, Korea;
10
Departments of Biochemistry and Chemistry, Brandeis University, Waltham, MA 02453; Helen and Robert Appel Alzheimer's Disease Research Institute, Weill Cornell Medical College, New York, NY 10065 kskim@mclean.harvard.edu chkim@mclean.harvard.edu gpetsko@med.cornell.edu.
11
Molecular Neurobiology Lab, McLean Hospital and Program in Neuroscience, Harvard Medical School, Belmont, MA 02478; kskim@mclean.harvard.edu chkim@mclean.harvard.edu gpetsko@med.cornell.edu.

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.

KEYWORDS:

NR4A2; Nurr1; Parkinson's disease; agonist; drug target

PMID:
26124091
PMCID:
PMC4507186
DOI:
10.1073/pnas.1509742112
[Indexed for MEDLINE]
Free PMC Article

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