//////What is NURR1?
Nuclear receptor related 1 protein (Nurr1) is an important transcription factor required for differentiation and maintenance of midbrain dopaminergic (DA) neurons. Since decrease in Nurr1 function either due to diminished expression or rare mutation is associated with Parkinson's disease (PD), upregulation of Nurr1 may be beneficial for PD. 1 2
NURR1 regulates gene expression linked to dopaminergic neuron genesis and functional maintenance. In addition to playing a key role in developing and maintaining neurotransmitter phenotypes in dopaminergic neurons, NURR1 agonists have been shown to reverse behavioral and histological abnormalities in animal PD models. 3
Thus, Nurr1 has been referred to play a pivotal role in both the differentiation of dopaminergic neurons in embryonic stages and the maintenance of the dopaminergic phenotype throughout life. 4
Numerous studies have documented that orphan nuclear receptor plays important roles in the midbrain dopamine (DA) neuron development, differentiation, and survival. 2 5
Further, Nurr1 engages in synthesizing and storing dopamine through regulating levels of tyrosine hydroxylase (TH), dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2).5
/////////////BASIC SCIENCE KNOCKOUT MICE
A constant metabolism and energy supply are crucial to all organs, particularly the brain. Age-dependent neurodegenerative diseases, such as Parkinson's disease (PD), are associated with alterations in cellular metabolism. 6
A knockout mouse is a laboratory mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA. 7 By knocking out the specific NURR1 gene, researchers are able to determine its function based on observing the signs, symptoms and illness seen in the genetically modified animal.
NURR1 is an orphan member of the nuclear receptor superfamily of transcription factors, is a major risk factor in the pathogenesis of PD, and changes in NURR1 expression can have a detrimental effect on cellular metabolism. Recent evidence suggests a vital role of NURR1 in dopaminergic (DAergic) neuron development and the pathogenesis of PD. 6
In this study, when Nurr1 was found to be down-regulated, CCL2 was up-regulated in PD patients and PD mice. CCL2 promoted apoptosis and secretion of inflammatory chemicals in cells and inhibited cell viability. Whereas knockdown of CCL2 exerted the opposite effects. 8
Nurr1 overexpression inhibited apoptosis, the release of pro-inflammatory TNF-α and IL-1β and promoted viability in α-Syn-treated SH-SY5Y cells. 8
Nurr1 overexpression also remarkably relieved movement disorder and spatial memory deficits and played neuroprotective and anti-inflammatory roles in MPTP-induced PD mice. 8
Nurr1 overexpression exerts neuroprotective and anti-inflammatory roles via down-regulating CCL2 in both in vivo and in vitro PD models, contributing to developing mechanism-based and neuroprotective strategies against PD. 8
////////////NURR1 ALPHA SYNUCLEIN
The expression level of Nurr1 has been proposed to be modulated by α-synuclein (α-SYN), an important pathological hallmark of PD. However, the underlying molecular mechanisms of α-SYN-Nurr1 interaction are still rarely explored. 9
Results of this study showed that overexpression of α-SYN reduced Nurr1 and its downstream gene expressions. α-SYN neither affected the mRNA stability nor bound with the promoter of Nurr1, but modulated the transcription activity of the Nurr1 promoter region. 9
Moreover, overexpression of α-SYN down-regulated NF-κB expression level, thereby inhibiting the transcription factor activity of NF-κB and decreasing the binding quantity of NF-κB with the Nurr1 promoter. 9
Mutations of the SNCA gene locus, which is related to encoding alpha-synuclein (ASYN), and loss of function mutations/knockout of Nurr1, a nuclear receptor responsible for guiding midbrain dopaminergic neuron development, are associated with familial Parkinson's disease (PD). As we age, the expression levels of these two genes in midbrain dopaminergic neurons follow opposite directions as ASYN expression increases while the expression of Nurr1 decreases. 10
We investigated the effect of ASYN and Nurr1 age-related expression alterations in the pathogenesis of PD by coupling Nurr1 hemizygous with ASYN(s) (heterozygote) or ASYN(d) (homozygote) transgenic mice. ASYN(d)/Nurr1+/- (2-hit) mice, contrary to the individual genetic traits, developed phenotypes consistent with dopaminergic dysfunction. 10
Aging '2-hit' (overexpressing ASYN, while under expressing NURR1) mice manifested kyphosis, severe rigid paralysis, L-DOPA responsive movement impairment and cachexia and died prematurely. 10
Pathological abnormalities of these mice included Substantia Nigra neuron degeneration, extensive neuroinflammation and enhanced ASYN aggregation. 10
Mice that overexpressed both Nurr1 and ASYN or with reduced ASYN load with normal NURR1 expression did not show this pathology. 10
Taken together these experiments demonstrate that ASYN-dependent PD-related pathophysiology is mediated at least in part by Nurr1 down-regulation. 10
Findings such as these may give us new insights to better understand the molecular mechanisms underlying the α-SYN-regulated Nurr1 function, which may stimulate further investigation into the mechanism of dopamine neuron degeneration in PD pathogenesis.9
/////////Neural Inflammation
Neuroinflammation plays a crucial role in the progression of neurodegenerative disorders, particularly Parkinson's disease (PD). Glial cell activation and subsequent adaptive immune involvement are neuroinflammatory features in familial and idiopathic PD, resulting in the death of dopaminergic neuron cells. 3
Neural stem cells (NSCs) are the most promising cells for cell replacement therapy for Parkinson's disease (PD). However, a majority of the transplanted NSCs differentiated into glial cells, thereby limiting the clinical application. 4
Most of the genes causing PD are also expressed in astrocytes and microglia, converting their neuroprotective role into a pathogenic one and contributing to disease onset and progression. 3
Previous studies indicated that chronic neuroinflammation plays a vital role in the degeneration of midbrain DA (mDA) neurons, which suggested the developing potential of therapies for PD by targeting the inflammatory processes. 4
Studies suggest that Nurr1 exerted anti-inflammatory effects and promoted the differentiation of NSCs into dopaminergic neurons. 4
NURR1 protects dopaminergic neurons from inflammation-induced degeneration, specifically attenuating neuronal death by suppressing the expression of inflammatory genes in microglia and astrocytes. 3
Experimental results suggest that Nurr1 protects dopaminergic neurons from neuroinflammation insults by limiting the production of neurotoxic mediators by microglia which promotes the survival of transplanted NSCs. 4
These findings provide a new theoretical and experimental foundation for the transplantation of Nurr1-overexpressed NSCs or that suppressing neuroinflammation with a variety of NURR1 targeted medications can effectively slow the progression of chronic neuroinflammation-induced PD. 3 4
///////NURR1 INDUCTION
Current treatments for Parkinson's disease (PD) are mainly dopaminergic drugs. However, dopaminergic drugs are only symptomatic treatments and limited by several side effects. 11
Recent studies into drug development focused on emerging new molecular mechanisms, including nuclear receptor-related 1 (Nurr1), adenosine receptor A2, nicotine receptor, metabotropic glutamate receptors and glucocerebrosidase. 11
Emerging evidence from in vitro and in vivo studies has recently demonstrated that Nurr1-activating compounds and Nurr1 gene therapy are able not only to enhance DA neurotransmission but also to protect DA neurons from cell injury induced by environmental toxin or microglia-mediated neuroinflammation. 2
Moreover, modulators that interact with Nurr1 or regulate its function, have the potential to enhance the effects of Nurr1-based therapies in PD. 2
This study underlines the importance of peroxisome proliferator-activated receptor (PPAR)α in controlling the transcription of Nurr1. 1
The mRNA analyses followed by different immunoassays clearly indicate that the PPARα agonist gemfibrozil, strongly upregulated the expression of Nurr1 in DA neurons. 1
To confirmed that PPARα was indeed involved in the expression of Nurr1, oral administration of gemfibrozil increased Nurr1 expression in vivo in nigra of wild-type, but not PPARα knockout mice. Thus identifying PPARα as a novel regulator of Nurr1 expression and associated protection of DA neurons. 1
The association between NURR1 and cellular metabolic abnormalities and its implications for PD therapy have been highlighted.6
//////////////// Melatonin
Melatonin, a highly lipophilic molecule secreted by the pineal gland in the brain, plays a role in various biological functions. Previous studies reported that melatonin exerts its effect on mesenchymal stem cell (MSC) survival and differentiation into osteogenic- and adipogenic-lineage. However, the effect of melatonin in neurogenic differentiation in amniotic fluid (AF)-MSCs remains to be explored, 12
Researchers have reported the induction of glial cell line-derived neurotrophic factor, a potent survival factor for dopaminergic neurons, in the C17.2 neural stem cells following in vitro treatment with melatonin. Furthermore, they have detected the melatonin MT(1) receptor in these cells. 13
In order to extend preliminary evidence of a potential role for melatonin in epigenetic modulation, its effects on the mRNA expression of several histone deacetylase (HDAC) isoforms and on histone acetylation were examined. 13
Physiological concentrations of melatonin (nanomolar range) increased neurite-like extensions and induced mRNA expression of the orphan nuclear receptor nurr1. 13
It is likely that the MT(1) receptor is involved in mediating these physiological effects of melatonin. These findings suggest novel roles for melatonin in stem cell differentiation and epigenetic modulation of gene transcription. 13
Melatonin was associated with ncreases in the levels of neuronal protein marker (βIII-tubulin) and dopaminergic neuronal markers (tyrosine hydroxylase, TH and NURR1), but decrease in the level of glial fibrillary acidic protein (GFAP), were observed in melatonin-treated AF-MSCs. 12
The levels of TH, NURR1 and dopamine transporter (DAT) were significantly increased in all treated groups when compared with control-untreated cells. 12
Pretreated AF-MSCs with MT1/MT2 receptors antagonist, diminished melatonin-induced increase in dopaminergic neuronal markers 12
/////////// astragalus extracts
Neural stem cells (NSCs) are important cellular sources of transplantation therapies for Parkinson's disease. This study aimed to determine the effects of extracts of radix astragali on the proliferation and differentiation into dopamine (DA) neurons in NSCs.
The study results showed that astragalus extracts had positive effects on the proliferation of NSCs. 14 and could promote the expressions of tyrosine hydroxylase and dopamine transporter mRNA, which are specifically expressed in DA neurons. 14
Nurr1, and pituitary homeobox 3 (Ptx3) are considered to promote the formation of DA neurons. 14
Results demonstrated that astragalus extracts can also promote the expressions Nurr1, mRNAs. 14
//////Bupleurum Peony Angelica BPA
The aim of this study was to investigate the protective effects of a herbal extract combination, consisting of Bupleurum falcatum, Paeonia suffruticosa, and Angelica dahurica (BPA), induced PD-like symptoms and to elucidate possible mechanisms of action focusing on Nurr1.5
BPA treatment induced increasing protein expression levels of Nurr1 and ultimately the levels of TH, VMAT2, and DAT. These results indicate that BPA has protective effects on dopaminergic neurons in a mouse model of PD by regulating Nurr1. 5
//////// SUMMARY
NURR1 is basically an “on” switch that can stimulate the genes that create and support dopamine producing cells in the brain. A number of studies suggest that increasing NURR1 can promote the development of neural stem cells into functioning dopamine producing neurons. NURR1 appears to restore and regrow, in particular, dopamine producing neurons, working at the gene level. Melatonin and the herb astragalus seem to elevate and promote the activity of NURR1. So does the herbal combination of Bupleurum Peony Angelica. This is encouraging!
////////References
1. Gottschalk, C. G., Roy, A., Jana, M., Kundu, M. & Pahan, K. Activation of Peroxisome Proliferator-Activated Receptor-α Increases the Expression of Nuclear Receptor Related 1 Protein (Nurr1) in Dopaminergic Neurons. Mol. Neurobiol. 56, 7872–7887 (2019).
2. Dong, J., Li, S., Mo, J.-L., Cai, H.-B. & Le, W.-D. Nurr1-Based Therapies for Parkinson’s Disease. CNS Neurosci. Ther. 22, 351–359 (2016).
3. Al-Nusaif, M., Lin, Y., Li, T., Cheng, C. & Le, W. Advances in NURR1-Regulated Neuroinflammation Associated with Parkinson’s Disease. Int. J. Mol. Sci. 23, 16184 (2022).
4. Chen, X.-X. et al. Nurr1 promotes neurogenesis of dopaminergic neuron and represses inflammatory factors in the transwell coculture system of neural stem cells and microglia. CNS Neurosci. Ther. 24, 790–800 (2018).
5. Sim, Y. et al. Protective effects of a herbal extract combination of Bupleurum falcatum, Paeonia suffruticosa, and Angelica dahurica against MPTP-induced neurotoxicity via regulation of nuclear receptor-related 1 protein. Neuroscience 340, 166–175 (2017).
6. Al-Nusaif, M., Yang, Y., Li, S., Cheng, C. & Le, W. The role of NURR1 in metabolic abnormalities of Parkinson’s disease. Mol. Neurodegener. 17, 46 (2022).
7. Knockout Mice Fact Sheet. Genome.gov genome.gov/about-genomics/f... (2022).
8. Liu, W., Gao, Y. & Chang, N. Nurr1 overexpression exerts neuroprotective and anti-inflammatory roles via down-regulating CCL2 expression in both in vivo and in vitro Parkinson’s disease models. Biochem. Biophys. Res. Commun. 482, 1312–1319 (2017).
9. Jia, C. et al. α-Synuclein Negatively Regulates Nurr1 Expression Through NF-κB-Related Mechanism. Front. Mol. Neurosci. 13, 64 (2020).
10. Argyrofthalmidou, M. et al. Nurr1 repression mediates cardinal features of Parkinson’s disease in α-synuclein transgenic mice. Hum. Mol. Genet. 30, 1469–1483 (2021).
11. Zhang, C.-L., Han, Q.-W., Chen, N.-H. & Yuan, Y.-H. Research on developing drugs for Parkinson’s disease. Brain Res. Bull. 168, 100–109 (2021).
12. Phonchai, R. et al. Potential effects and molecular mechanisms of melatonin on the dopaminergic neuronal differentiation of human amniotic fluid mesenchymal stem cells. Neurochem. Int. 124, 82–93 (2019).
13. Sharma, R., Ottenhof, T., Rzeczkowska, P. A. & Niles, L. P. Epigenetic targets for melatonin: induction of histone H3 hyperacetylation and gene expression in C17.2 neural stem cells. J. Pineal Res. 45, 277–284 (2008).
14. Gao, H., Dou, L., Shan, L., Sun, Y. & Li, W. Proliferation and committed differentiation into dopamine neurons of neural stem cells induced by the active ingredients of radix astragali. Neuroreport 29, 577–582 (2018).
Stem Cell therapy for PD
Stem cell treatment Parkinson’s 
Gastrodin protects dopaminergic neurons via insulin-like pathway in a Parkinson’s disease model
Active recruitment for stem cell trial
