title: Nuclear receptor Nurr1 agonists enhance its dual functions and improve behavioral deficits in an animal model of Parkinson's disease.
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.
authors.affiliation: 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.
authors.forename: Chun-Hyung
authors.initials: CH
authors.lastname: Kim
authors.affiliation: 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;
authors.forename: Baek-Soo
authors.initials: BS
authors.lastname: Han
authors.affiliation: 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;
authors.forename: Jisook
authors.initials: J
authors.lastname: Moon
authors.affiliation: Molecular Neurobiology Lab, McLean Hospital and Program in Neuroscience, Harvard Medical School, Belmont, MA 02478;
authors.forename: Deog-Joong
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore;
authors.forename: Joon
authors.initials: J
authors.lastname: Shin
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore;
authors.forename: Sreekanth
authors.initials: S
authors.lastname: Rajan
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore;
authors.forename: Quoc Toan
authors.initials: QT
authors.lastname: Nguyen
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea;
authors.forename: Mijin
authors.initials: M
authors.lastname: Sohn
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea;
authors.forename: Won-Gon
authors.initials: WG
authors.lastname: Kim
authors.affiliation: Molecular Neurobiology Lab, McLean Hospital and Program in Neuroscience, Harvard Medical School, Belmont, MA 02478;
authors.forename: Minjoon
authors.initials: M
authors.lastname: Han
authors.affiliation: Molecular Neurobiology Lab, McLean Hospital and Program in Neuroscience, Harvard Medical School, Belmont, MA 02478;
authors.forename: Inhye
authors.initials: I
authors.lastname: Jeong
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea;
authors.forename: Kyoung-Shim
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea;
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Lee
authors.affiliation: Departments of Biochemistry and Chemistry, Brandeis University, Waltham, MA 02453;
authors.forename: Yupeng
authors.initials: Y
authors.lastname: Tu
authors.affiliation: Departments of Biochemistry and Chemistry, Brandeis University, Waltham, MA 02453;
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: Naffin-Olivos
authors.affiliation: Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea;
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Park
authors.affiliation: Departments of Biochemistry and Chemistry, Brandeis University, Waltham, MA 02453;
authors.forename: Dagmar
authors.initials: D
authors.lastname: Ringe
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore; Department of Genetic Engineering, College of Life Sciences, Kyung Hee University, Seoul, Korea;
authors.forename: Ho Sup
authors.initials: HS
authors.lastname: Yoon
authors.affiliation: 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.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Petsko
authors.affiliation: 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.
authors.forename: Kwang-Soo
authors.initials: KS
authors.lastname: Kim
mesh_terms: D000655:Amodiaquine / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002738:Chloroquine / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D008024:Ligands; D055495:Neurogenesis; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000819:agonists* / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy / Q000473:pathology / Q000523:psychology*; D051381:Rats
chemical_list: D008024:Ligands; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D000655:Amodiaquine; D002738:Chloroquine; D016627:Oxidopamine
keywords: NR4A2; Nurr1; Parkinson's disease; agonist; drug target