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

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...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 112; no. 28; pp. 8756 - 8761
Main Authors 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
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 14.07.2015
National Acad Sciences
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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.
AbstractList 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.
Parkinson’s disease (PD) is the most prevalent movement disorder with no available treatments that can stop or slow down the disease progress. Although the orphan nuclear receptor Nurr1 is a promising target for PD, it is thought to be a ligand-independent transcription factor and, so far, no small molecule has been identified that can bind to its ligand binding domain. Here, we established high throughput cell-based assays and successfully identified three Nurr1 agonists among FDA-approved drugs, all sharing an identical chemical scaffold. Remarkably, these compounds not only directly bind to Nurr1 but also ameliorate behavioral defects in a rodent model of PD. Thus, our study shows that Nurr1 could serve as a valid drug target for neuroprotective therapeutics of PD. 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.
Author Tu, Yupeng
Nguyen, Quoc Toan
Han, Baek-Soo
Kim, Deog-Joong
Rajan, Sreekanth
Petsko, Gregory A.
Kim, Chun-Hyung
Han, Minjoon
Ringe, Dagmar
Park, Chang-Hwan
Yoon, Ho Sup
Kim, Kwang-Soo
Shin, Joon
Sohn, Mijin
Kim, Kyoung-Shim
Lee, Eun-Hye
Moon, Jisook
Jeong, Inhye
Kim, Won-Gon
Naffin-Olivos, Jacqueline L.
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  organization: School of Biological Sciences, Nanyang Technological University, Singapore
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  fullname: Rajan, Sreekanth
  organization: School of Biological Sciences, Nanyang Technological University, Singapore
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  organization: School of Biological Sciences, Nanyang Technological University, Singapore
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  organization: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
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  surname: Lee
  fullname: Lee, Eun-Hye
  organization: Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea
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  givenname: Yupeng
  surname: Tu
  fullname: Tu, Yupeng
  organization: Departments of Biochemistry and Chemistry, Brandeis University, Waltham, MA 02453
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  givenname: Jacqueline L.
  surname: Naffin-Olivos
  fullname: Naffin-Olivos, Jacqueline L.
  organization: Departments of Biochemistry and Chemistry, Brandeis University, Waltham, MA 02453
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  surname: Park
  fullname: Park, Chang-Hwan
  organization: Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea
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  surname: Yoon
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  organization: School of Biological Sciences, Nanyang Technological University, Singapore
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  organization: Helen and Robert Appel Alzheimer’s Disease Research Institute, Weill Cornell Medical College, New York, NY 10065
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/26124091$$D View this record in MEDLINE/PubMed
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Keywords NR4A2
Nurr1
agonist
Parkinson's disease
drug target
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1C.-H.K., B.-S.H., J.M., and D.-J.K. contributed equally to this work.
Author contributions: C.-H.K., G.A.P., and Kwang-Soo Kim designed research; C.-H.K., B.-S.H., J.M., D.-J.K., M.H., and E.-H.L. performed research; C.-H.K., J.S., S.R., Q.T.N., and M.S. contributed new reagents/analytic tools; C.-H.K., M.S., W.-G.K., I.J., Kyoung-Shim Kim, Y.T., J.L.N.-O., C.-H.P., D.R., and H.S.Y. analyzed data; and C.-H.K., G.A.P., and Kwang-Soo Kim wrote the paper.
Contributed by Gregory A. Petsko, May 28, 2015 (sent for review August 1, 2013)
OpenAccessLink https://www.pnas.org/content/pnas/112/28/8756.full.pdf
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Snippet Parkinson’s disease (PD), primarily caused by selective degeneration of midbrain dopamine (mDA) neurons, is the most prevalent movement disorder, affecting...
Parkinson's disease (PD), primarily caused by selective degeneration of midbrain dopamine (mDA) neurons, is the most prevalent movement disorder, affecting...
Parkinson’s disease (PD) is the most prevalent movement disorder with no available treatments that can stop or slow down the disease progress. Although the...
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SubjectTerms Amodiaquine - metabolism
Amodiaquine - pharmacology
Animal behavior
Animals
Behavior, Animal - drug effects
Binding sites
Biological Sciences
Chloroquine - metabolism
Chloroquine - pharmacology
Disease Models, Animal
Dopamine
Gene expression
Ligands
Molecules
Neurogenesis
Neurons
Nuclear Receptor Subfamily 4, Group A, Member 2 - agonists
Nuclear Receptor Subfamily 4, Group A, Member 2 - metabolism
Oxidopamine - toxicity
Parkinson Disease - drug therapy
Parkinson Disease - pathology
Parkinson Disease - psychology
Parkinson's disease
Rats
Rodents
Title Nuclear receptor Nurr1 agonists enhance its dual functions and improve behavioral deficits in an animal model of Parkinson’s disease
URI https://www.jstor.org/stable/26466034
http://www.pnas.org/content/112/28/8756.abstract
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Volume 112
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