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Title 

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

Authors 

C H KimBaek Soo HanJ MoonD J KimJ ShinS RajanQ T NguyenMi-Jin SohnWon Gon KimM HanI JeongKyoung Shim KimE H LeeY TuJ L Naffin-OlivosC H ParkD RingeH S YoonG A PetskoK S Kim

Publisher 

National Academy of Sciences

Issue Date 

2015

Citation 

Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 28, pp. 8756-8761

Keywords 

AgonistDrug targetNR4A2Nurr1Parkinson'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.

ISSN 

0027-8424

Link 

http://dx.doi.org/10.1073/pnas.1509742112

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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