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.
Pharmacology, Toxicology and Pharmaceutical Science
11
6%
Other
25
13%
Unknown
69
35%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 121. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 14 August 2025.
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#440,263
of 34,400,738 outputs
Outputs from Proceedings of the National Academy of Sciences of the United States of America
#7,285
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Outputs of similar age
#3,810
of 302,951 outputs
Outputs of similar age from Proceedings of the National Academy of Sciences of the United States of America
#70
of 892 outputs
Altmetric has tracked 34,400,738 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 98th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 118,992 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 40.1. This one has done particularly well, scoring higher than 93% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 302,951 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 98% of its contemporaries.
We're also able to compare this research output to 892 others from the same source and published within six weeks on either side of this one. This one has done particularly well, scoring higher than 92% of its contemporaries.
