"The orphan nuclear receptor Nurr1 is critical for the development, maintenance and protection of midbrain dopaminergic (mDA) neurons. Here we show that prostaglandin E1 (PGE1) and its dehydrated metabolite, PGA1, directly interact with the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional function. We also report the crystallographic structure of Nurr1-LBD bound to PGA1 at 2.05 Å resolution. PGA1 couples covalently to Nurr1-LBD by forming a Michael adduct with Cys566, and induces notable conformational changes, including a 21° shift of the activation function-2 helix (H12) away from the protein core. Furthermore, PGE1/PGA1 exhibit neuroprotective effects in a Nurr1-dependent manner, prominently enhance expression of Nurr1 target genes in mDA neurons and improve motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse models of Parkinson’s disease. Based on these results, we propose that PGE1/PGA1 represent native ligands of Nurr1 and can exert neuroprotective effects on mDA neurons, via activation of Nurr1’s transcriptional function."
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"Two compounds with hormone-like effects — prostaglandin E1 (PGE1) and prostaglandin A1 (PGA1) — may help to increase dopamine levels in the brain and slow Parkinson’s progression by activating a protein, called Nurr1, that supports dopaminergic neurons, a study reports.
The study, “PGE1 and PGA1 bind to Nurr1 and activate its transcriptional function,” was published in the journal Nature Chemical Biology.
Prostaglandins have various roles in controlling body functions, such as the contraction and relaxation of smooth muscle, the dilation and constriction of blood vessels, blood pressure control, and modulating inflammation.
Nurr1 is a protein that plays a key role in the development and maintenance of midbrain dopaminergic neurons — those that produce dopamine and are gradually lost throughout Parkinson’s disease. It does so by inducing the expression of genes that are essential for dopamine production and nerve cell survival.
A previous study found that Nurr1 was present at lower levels in the substantia nigra (a brain region rich in dopaminergic neurons) of Parkinson’s patients, suggesting Nurr1 could be a therapeutic target for treating the condition.
Scientists at Nanyang Technological University in Singapore (NTU Singapore) and Harvard University set out to identify molecules that may bind to Nurr1 and activate its protective properties.
“Considering the essential function of Nurr1, we have been searching for its activating molecules in the body,” Yoon Ho Sup, a professor at the NTU School of Biological Sciences and study author, said in a press release.
The team identified PGE1 and PGA1 as two molecules able to bind to Nurr1. Using dopaminergic neurons derived from rodents, researchers further observed that PGE1 and PGA1 were able to induce the expression of Nurr1’s target genes, increase dopamine levels, and protect against cell death.
Of note, gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.
Treatment with PGE1 and PGA1 was seen to significantly lessened motor symptoms in a mouse model of Parkinson’s disease.
While PGE1-treated mice showed a more extensive recovery of motor function than PGA1-treated mice, both PGE1 and PGA1 protected dopaminergic neurons in the substantia nigra from cell death. Dopamine levels were also increased by both prostaglandins.
“We have successfully identified that PGE1/PGA1 is the molecular pair that acts specifically on Nurr1 and can lead to neuroprotective effects on the brain,” Yoon said.
Data also suggest “that native and/or synthetic ligands of Nurr1 may be developed as a novel class of mechanism-based neuroprotective drugs for PD [Parkinson’s disease] and other human disorders involving Nurr1 dysfunction,” the researchers wrote.
“Given that all candidate Parkinson’s drugs have failed to show neuroprotective abilities in clinical trials, our findings may offer an opportunity to design mechanism-based disease-modifying therapeutics to treat Parkinson’s disease with little side effect,” Yoon said.
“PGA1 is not a new kid on the block, but a molecule known to exhibit anti-inflammation and anti-tumour properties. Prostaglandins like PGE1 are available for clinical use, for example in obstetrics cases. This means that the compound can potentially be re-positioned to treat Parkinson’s patients, which can accelerate the time needed to take an experimental drug to the clinic,” added Lim Kah Leong, vice dean of research at the NTU Lee Kong Chian School of Medicine."
"Prof Kim said, "By uncovering the molecular interactions, we gain insights into the biological function and regulation of Nurr1 in health and disease such as Parkinson's disease. Our findings in this study are adding to what we know about how dopamine neurons function and point towards the development of novel therapeutics of Parkinson's disease."
Highlighting the significance of the findings, co-author Professor Lim Kah Leong, Vice Dean (Research) of NTU Lee Kong Chian School of Medicine said, "PGA1 is not a new kid on the block, but a molecule known to exhibit anti-inflammation and anti-tumour properties. Prostaglandins like PGE1 are available for clinical use, for example in obstetrics cases. This means that the compound can potentially be re-positioned to treat Parkinson's patients, which can accelerate the time needed to take an experimental drug to the clinic."
The scientists are now looking to design a synthetic form of PGE1/PGA1 and to validate it as a potential new drug that can target Nurr1, thereby halting or reversing the onset of Parkinson's disease."
Prostaglandin A2 Interacts with Nurr1 and Ameliorates Behavioral Deficits in Parkinson's Disease Fly Model 2022 pubmed.ncbi.nlm.nih.gov/354...
"The orphan nuclear receptor Nurr1 is critical for the development, maintenance, and protection of midbrain dopaminergic neurons. Recently, we demonstrated that prostaglandins E1 (PGE1) and PGA1 directly bind to the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional activation function. In this direction, here we report the transcriptional activation of Nurr1 by PGA2, a dehydrated metabolite of PGE2, through physical binding ably supported by NMR titration and crystal structure. The co-crystal structure of Nurr1-LBD bound to PGA2 revealed the covalent coupling of PGA2 with Nurr1-LBD through Cys566. PGA2 binding also induces a 21° shift of the activation function 2 (AF-2) helix H12 away from the protein core, similar to that observed in the Nurr1-LBD-PGA1 complex. We also show that PGA2 can rescue the locomotor deficits and neuronal degeneration in LRRK2 G2019S transgenic fly models."
Potent synthetic and endogenous ligands for the adopted orphan nuclear receptor Nurr1 2021 nature.com/articles/s12276-...
"Conclusion and perspective
In this review, we introduced recent findings on potent synthetic and endogenous ligands of Nurr1 ligands, a nuclear receptor that has long been referred to as a ligand-independent nuclear receptor (Tables 1, 2). The actions of these activators and ligands strongly support the notion that Nurr1 is not an orphan nuclear receptor that is constitutively active in a ligand-independent manner. Recent in-depth characterization of the structural conformations of Nurr1-LBD and ligand-bound crystal structures further provides molecular and structural insights into the ligand-dependent roles of Nurr1 under physiological and pathological conditions. The dopamine oxidation metabolite DHI has been proposed as a regulatory factor in intracellular dopamine homeostasis through Nurr1 activation (Fig. 3). In addition, PGE1 and PGA1 have been proposed to mediate neuroprotection via activation of Nurr1 in neurodegenerative diseases such as PD and AD. It is likely that extracellular PGE1 regulates the transcriptional activity of Nurr1 via the EP2-mediated pathway, whereas intracellular PGE1/PGA1 bind directly to Nurr1-LBD, activating its transcriptional function (Fig. 4). While the EP2-mediated cAMP-dependent pathway may regulate Nurr1 function by upregulating its expression70,71, it is also possible that Nurr1’s protein stability and/or transcriptional activity may be regulated by altered levels of intracellular cAMP. Further studies are warranted for clarification of these mechanisms as well as for therapeutic development of these Nurr1 ligands."
So... they have molecules they think would slow the progression of PD, and this is the final line:
"The team is now focused to enhance both chloroquine and amodiaquine therapeutic activity for PD, eventually testing these drugs in future clinical trials for PD."
I would think they would be testing what they have now.
The results, published in the journal Neurology, showed that chloroquine and hydroxychloroquine were associated with a 26 percent decreased risk of Parkinson's. They did not find a similar link for other arthritis medications, such as methotrexate.Jan 28, 2022
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