Nurr1‐Based Therapies for Parkinson's Disease

Summary

Previous studies have documented that orphan nuclear receptor Nurr1 (also known as NR4A2) plays important roles in the midbrain dopamine (DA) neuron development, differentiation, and survival. Furthermore, it has been reported that the defects in Nurr1 are associated with Parkinson's disease (PD). Thus, Nurr1 might be a potential therapeutic target for PD. 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. Moreover, modulators that interact with Nurr1 or regulate its function, such as retinoid X receptor, cyclic AMP‐responsive element‐binding protein, glial cell line‐derived neurotrophic factor, and Wnt/β‐catenin pathway, have the potential to enhance the effects of Nurr1‐based therapies in PD. This review highlights the recent progress in preclinical studies of Nurr1‐based therapies and discusses the outlook of this emerging therapy as a promising new generation of PD medication.

Introduction

Parkinson's disease (PD), affecting 1.5% of the global population aged over 65 years 1, is a common neurodegenerative disease characterized by the progressive loss of dopamine (DA) neurons in the substantia nigra (SN) pars compacta and the striatal DA deficiency. The main clinical manifestations of PD, including bradykinesia, rigidity, resting tremor, postural instability, and nonmotor symptoms, seriously impair patients’ quality of life. Although the pathogenesis of PD is still far from being clearly understood, it has been accepted that the occurrence of PD might attribute to the interplay of genetic and environmental factors 2. Until now, at least 15 causal genes have been identified to be related to PD, such as α‐synuclein, parkin, LARRK2, PINK, and DJ1 3. In addition, exposure to certain environmental toxins, such as 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), rotenone, and paraquat, has been found to increase the risk of developing PD. Pathologically, PD has also been characterized by the presence of Lewy bodies containing aggregated and misfolded α‐synuclein. Moreover, neuroinflammation, reactive oxygen species, mitochondrial dysfunction, and autophagy or proteasome system impairment are considered as major pathogenic contributors to PD 4, 5, 6.

Current available PD therapies are mainly aimed at ameliorating motor symptoms associated with DA deficiency, including levodopa, DA agonists, catechol‐O‐methyltransferase inhibitors, and monoamine oxidase‐B inhibitors 7. Unfortunately, the current pharmaceutical treatments cannot prevent the degeneration of DA neurons and usually lose their efficacy over time, while often accompany severe side effects such as dyskinesia, on–off fluctuation, and peripheral reactions. Other medications such as deep brain stimulation, cell transplantation, and gene therapy have limitations too, concerning the surgery risk and potential safety hazard. In addition, the symptomatic alleviating effects from alternative therapies lack robust improvement, so that they usually just serve as adjunctive medications in clinic. In general, none of these treatments can either slow the disease progression or maintain the viability and functions of DA neurons 8. Therefore, mechanism‐based and/or disease‐modifying therapies are in urgent need for better management of PD progression. For example, several preclinical tests of molecular targeted therapies have been conducted and the results seem promising 8. It is highly speculated that these therapies may not only have symptomatic effects, but also provide neuroprotective and neurorepairable benefits in the treatment of PD 8. Among those, Nurr1‐based therapies for PD have attracted great attention. Thus, in this review, we will highlight the progress of several potential Nurr1‐based strategies, including Nurr1‐activating compounds and Nurr1 gene therapy, hoping that they may become future medication against PD.

Identifying Nurr1 as a Therapeutic Target of PD

Functions of Nurr1 in DA Neurons

Nurr1 (also known as NR4A2) is a member of NR4A subgroup of nuclear receptor superfamily. The other two members in NR4A subgroup are Nur77 (NR4A1) and Nor1 (NR4A3), which may possess quite different functions as compared with Nurr1 9. There are many studies demonstrating that Nurr1 plays an essential role in the development, differentiation, maintenance, and survival of midbrain DA neurons that are mostly affected in the brain of PD 10. Nurr1, as a transcriptional factor, seems to express earlier than numerous phenotypic markers of DA neurons, such as tyrosine hydroxylase (TH), DA transporter (DAT), aromatic amino acid carboxylase (AADC), and vesicular monoamine transporter (VMAT) 10, 11. There is an age‐dependent reduction in Nurr1 expression in the midbrain DA neurons, which arouses much interest because it may possibly explain the high morbidity of PD in the elderly people 12, 13. In addition, it has been reported that Nurr1's immunoreactivity is significantly decreased in the SN of patients with PD 14, 15, 16 and numerous polymorphisms and mutations in Nurr1 have been identified to be associated with both familial and sporadic PD 17. In consistence with those clinical observations, preclinical studies have also demonstrated the essential role of Nurr1 in the midbrain DA neuron development and functional maintenance 11, 18, 19, 20, 21. Genetic deletion of Nurr1 in mice can cause the absence of DA neurons in the SN and ventral tegmental area, which may result in the death of the newborn mice 11. Several DA neuronal phenotypes such as TH and AADC that are important in the neurotransmission of nigrostriatal pathway are missing in Nurr1‐deficient mice 10. Meanwhile, the heterozygous Nurr1‐deficient mice show a higher susceptibility of DA neurons to neurotoxins and exert the similar age‐dependent DA dysfunction even before the DA neuron loss 18, 19, 20. Moreover, recent Nurr1 conditional ablation mice simulate the early features of PD, showing a series of pathological changes, including DA neuronal loss, striatal DA reduction, and motor deficiency, which could serve as suitable model to study PD 21.

It is clear that Nurr1 works as a transcriptional factor to regulate several genes involved in the DA neuronal phenotypes, ranging from the DA metabolism, neurotransmission, axonal growth, mitochondrial function, and cell survival 17, 21, 22, 23. More and more target genes have been found that are transcriptionally controlled by Nurr1 in DA neurons, including Dlk1, Ptpru, Klhl1, GTP, and VIP 24, 25, 26. Emerging evidence has suggested that there is a complicated network between Nurr1 and other essential transcriptional factors during the DA neuron development. Pix3 and Wnt/β‐catenin pathways are the two major signaling molecules contributing to the midbrain DA neurogenesis via cooperating with the Nurr1 transcription complex 27, 28, 29. In addition, the overexpression and accumulation of α‐synuclein may interrupt the function of Nurr1 through the direct or indirect interference with the signaling of glial cell line‐derived neurotrophic factor (GDNF), whose receptor proto‐oncogene tyrosine‐protein kinase receptor Ret is regulated by Nurr1 30, 31, and the interaction with α‐synuclein makes GDNF fail to exert neuroprotective effect in PD 32. In addition, mitochondrial dysfunction and the correlative oxidative phosphorylation impairment have been indicated as major risk factors of PD 5. In Nurr1‐ablated DA neurons, more than 90% of genes encoding respiratory chains are downregulated 21. More importantly, Saijo et al. 33 have recently identified a new pathogenic mechanism linking Nurr1 and PD, that is, the suppressive effect of Nurr1 in the production of inflammatory factors induced neuronal injury. Corepressor for repressor element 1 silencing transcription factor (CoREST) repressor complex is identified as an essential modulator in Nurr1‐mediated transrepression that inflammatory signals promote the recruitment of CoREST and Nurr1 to the p65 subunit of NF‐κB, resulting in the reduction in gene transcription of inflammatory factors 33. Interestingly, microglia and astrocytes seem to be the primary targets for the neuroprotective effects of Nurr1, rather than DA neurons themselves 33. These findings provide us an insight understanding of the effect of Nurr1 in PD pathogenesis and open a door for future research for the therapeutic strategies based on Nurr1.

Structure and Potential Activating Sites of Nurr1

Basically, Nurr1 is an immediate early gene and its transcription can be rapidly induced by various stimuli such as cAMP, inflammatory signals, hormones, calcium, and growth factors. These modulators can influence the Nurr1 expression by directly acting on the promoters or transcription regulatory element (cAMP‐response element, CArG‐like element, SP‐1 element) 34, 35. Nurr1, as a member of NR4A subfamily, shares similar structural features with Nur77 and Nor1, including (1) a modulator domain, referred to as activation function (AF)‐1 in the N‐terminus; (2) a conversed DNA‐binding domain (DBD); (3) ligand‐binding domain (LBD); and its transactivation‐dependent AF‐2 in the C‐terminus 9. The high conserved DBD has two zinc fingers, which is able to bind to nerve growth factor‐inducible β‐binding response element as monomer or homodimers, or Nur response element as homodimers, which are involved in the transcription process to activate TH and DAT genes 36, 37. In addition, Nurr1 and Nur77 can bind as monomers, homodimers, and heterodimers with retinoid X receptor (RXR). These RXR heterodimers bind a motif called DR5 and can be efficiently activated by RXR ligands 38. Unlike other nuclear receptors, NR4A subfamily does not have LBD cavity due to the occupation of several bulky hydrophobic residues 39. Instead, its transcriptional activity appears to be dependent on the AF‐1 domain 40. This feature of Nurr1 makes it difficult to discover compounds that can directly activate Nurr1 through LBD. However, several coregulator interaction surfaces in Nurr1 LBD have been identified, such as residues 592, 593, and 577, especially the groove between helices 11 and 12, which provides the possibility in developing Nurr1‐activating compounds based on their binding to LBD 41, 42. Furthermore, several compounds have already been identified to activate Nurr1 or Nur77 via their LBDs 43, 44, 45. In general, based on the activated functions of these regions of Nurr1 and numerous studies of Nurr1‐activating compounds, it is possible to identify small molecules activating a Nurr1 through its different domains.

Nurr1‐Activating Compounds

Great efforts have been taken to explore novel Nurr1‐activating compounds in recent years (as summarized in Table 1). These compounds can activate Nurr1 functions and further exert neuroprotective, neurogenic, or antiinflammatory effects.

Table 1.

The characteristics of Nurr1‐activating compounds

Mercaptopurine (6‐mercaptopurine or 6‐MP), an antileukemia drug, is the first identified Nurr1/Nor1 agonist from high‐throughput screening, which stimulates Nurr1/Nor1 through directly binding to the N‐terminal AF‐1 domain 46, 47. In addition to 6‐MP, a series of benzimidazole‐based compounds with Nurr1‐activating properties (EC₅₀: 8–70 nM) have been identified and synthesized 48. Given that no Nurr1 ligands have been found, a group of compounds with benzimidazole scaffold have been screened through a reporter gene (luciferase) assay, whose expression is regulated by Nurr1‐specific DNA‐binding elements. However, only the Nurr1 biological functions, not the antiparkinsonian effects of these compounds have been tested.

Previous reports have demonstrated that 1,1‐bis (3′‐indolyl)‐1‐(aromatic) methane (C‐DIM) analogs can influence the expression of NR4A subfamily in several cancer cells 49, 50, 51, 52. Recently, the antiparkinsonian effects of C‐DIM analogs have been identified. Interestingly, it shows similar activating capacities with different p‐substituted phenyl (OCH₃, CI, CF₃, Br, t‐Bu, CN, I, and OCF₃), suggesting a structure‐activating relation (SAR) existing in these compounds that contain a bis (3′‐indolyl) moiety. In addition, Li et al. have demonstrated that both N‐ and C‐terminal domains are involved in the activation of Nurr1, but without evidence to confirm the direct binding between C‐DIM analogs and Nurr1 52. Among these C‐DIM analogs, C‐DIM5 and C‐DIM8 have a higher affinity for Nur77 but with opposite effect 49, 51. After a comparative analysis, C‐DIM12 (higher affinity for Nurr1) has the most potent neuroprotective activity and antiinflammatory effect in MPTP‐lesioned rat model of PD 53. It could enhance the expressions of Nurr1 and Nurr1‐regulated proteins such as TH and DAT, and Nurr1‐mediated recruitment of CoREST and the NF‐κB‐mediated inflammatory gene expression are suppressed in SN 53, 54, 55.

Another Nurr1 activator, isoxazolo‐pyridinone 7e (IP7e), has been reported to attenuate the inflammation and neurodegeneration via inhibiting NF‐κB‐dependent process 56. IP7e seems to be a promising candidate due to its high oral bioavailability of 95% plus rapid and extensive brain absorption and distribution 57. However, the Nurr1‐activating effect of IP7e has only been tested in multiple sclerosis models, not in PD models. As for PD, the analog of isoxazolo‐pyridinone derivative, SH1, has been demonstrated to be effective to improve behavioral performance in lactacystin‐lesioned PD mouse model, of which inhibition of microglia‐mediated neuroinflammation and increasing the DA‐specific phenotypes may be the main mechanisms to explain its effect 58. In addition, SA00025, another novel Nurr1 agonist (EC₅₀: 2.5 nM), shows a partial neuroprotective effect in PD models induced by inflammatory stimulant poly (I:C) and 6‐hydroxydopamine (6‐OHDA). It can modulate several DA target genes and display antiinflammatory activity by reducing the activation of microglia and astrocytes 59.

While all the above compounds have been identified as Nurr1‐activating compounds, none of them are shown to activate Nurr1 by direct physical interaction with LBD. Strikingly, Kim et al. have recently identified antimalarial drugs amodiaquine (AQ) and chloroquine (CQ) together with a pain‐relieving drug glafenine as a novel group of Nurr1 activators and finally demonstrated that AQ/CQ (EC50: 20–50 μM) can interact with Nurr1‐LBD via direct physical binding [43]. They used a series of analyses, including Biacore S51 SPR sensor, fluorescence quenching analysis, a radioligand‐binding assay by [³H]‐CQ, and nuclear magnetic resonance to estimate this phenomenon. This finding advances our current understanding of the LBD binding properties and opens the door for further research and development of Nurr1 agonists. Interestingly, these compounds contain an identical 4‐amino‐7‐chloroquinoline scaffold, which may predict a possible SAR. As for the underlying mechanisms, the inhibition of microglia‐mediated neuroinflammation and increase in DA‐specific gene expression are involved in the antiparkinsonian effect of AQ/CQ. Moreover, the autophagy‐regulating effects of AQ/CQ may also predict potential interactions between Nurr1 and autophagy for their antiparkinsonian effects 60.

These Nurr1‐activating compounds provide much promising possibilities for PD treatment and most of them exert the antiparkinsonian effect through both the activating and suppressing functions of Nurr1. Although these compounds have the ability to activate Nurr1, it is still not clear the exact regions of Nurr1 targeted by these compounds. Among them, only 6‐MP and AQ have been confirmed to directly bind to the AF‐1 or LBD of Nurr1, so further studies are in urgent need to discover the specific binding regions on Nurr1. Furthermore, the pharmacodynamic and pharmacokinetic properties and the side effects of those compounds are also required to evaluate. As the other two members of NR4A subfamily, Nur77 and Nor1, share high similar structure with Nurr1, and they are both involved in the regulation of neurological functions and inflammation, it is of importance to test the specificity of the existing Nurr1‐activating compounds 61, 62. Wei et al. have recently indicated that Nurr1 and Nur77 might present a contradirectionally coupling interaction in memantine‐mediated neuroprotection 63. This complicated network makes it very difficult to predict the therapeutic outcome if both Nurr1 and its homologs are activated through the conserved regions. Moreover, SAR has been a research hotpot recently, especially after the presentation of the Nurr1‐activating effects of C‐DIM analogs and AQ/CQ. Meanwhile, we should notice the fact that subtle alternations of the functional structure might result in a great or even opposite effects 49, 51. Only after those concerns are well addressed, we might be able to determine whether Nurr1‐activating compounds can provide an alternative therapy for PD.

Nurr1 Modulators

In addition to activate Nurr1 by recognition on the specific target region of Nurr1, some other compounds, such as DA agonists, memantine, retinoic acid‐loaded polymeric nanoparticles (RA‐NPs), and herbal extracts (as summarized in Table 2), have also been demonstrated to upregulate Nurr1 expression in preclinical tests of PD treatment although there have not any report to confirm that they can activate Nurr1 by direct binding 63, 64, 65, 66, 67, 68, 69.

Table 2.

The characteristics of Nurr1 modulators

The neuroprotective effect of DA agonists has been a controversial topic for decades 70. One recent clinical trial supports that DA agonists can exert neuroprotection by inducing Nurr1 expression in peripheral blood mononuclear cells 71. Additionally, in DA neuron cell lines, D2/D3 agonist pramipexole has a profound effect to increase Nurr1 expression, which precedes the upregulation of DAT and VMAT2 expressions 64, suggesting that Nurr1 may serve as a key target for DA agonist‐mediated neuroprotection.

Memantine, an N‐methyl‐D‐aspartate receptor antagonist, has been demonstrated to restore PC12 cell survival from 6‐OHDA‐induced neurotoxicity through upregulating Nurr1 and downregulating Nur77 and partially inhibit migration of Nur77 from nucleus to mitochondria 63. Different from Nurr1, Nur77 usually triggers apoptotic process when migrates to mitochondria and induces inflammation via NF‐κB pathway 72, 73. Interestingly, administration of DA activators could decrease Nur77 expression 74, suggesting that Nurr1 together with the contradirectional coupling of Nurr1/Nur77 might be involved in PD pathogenesis.

Besides those chemically synthesized compounds, several Nurr1‐modulators from natural source, such as moracenin D, EGb 761, radicicol, and Bushen Huoxue decoction (BHD), are also effective in PD therapy 65, 66, 67, 68. Moracenin D, an extract from Mori Cortex radices, significantly upregulates Nurr1 expression and downregulates α‐synuclein expression 65. EGb 761, extracted from Ginkgo biloba leaves, has been applied in clinical trials of treating several neuropsychiatric diseases 75, 76. It also exerts neuroprotective effect in MPTP‐lesioned mice via increasing the expression of a series of DA‐related genes, of which Nurr1 is increased by 148% in SN 66. Our previous study has shown that radicicol could induce HSP70 expression in SH‐SY5Y cells against rotenone‐induced apoptosis through the inhibition of P53 and induction of Nurr1 67. It has been reported that the medical decoction BHD could also increase Nurr1 expression. The antiparkinsonian effect of BHD has been tested in clinical trials 68, 77.

Biomaterials as therapeutic tools have been developed to help Nurr1‐based PD therapy recently. Retinoic acid (RA) can enhance the survival and maturation of neuronal cells and RA receptors are highly expressed in DA neurons 78. In contrast to conventional RA formulations, the recently developed novel nanoparticles coupled with RA could rapidly transport into cells to release RA, and exert neuroprotection against DA neuronal damage in MPTP mouse model of PD. More importantly, RA‐NP administration increases the expression levels of Pitx3 and Nurr1, showing its supportive effect on the development and functional maintenance of DA neurons in PD 69.

Although the specific mechanisms for the Nurr1 upregulating effects of the above‐mentioned compounds, natural products, and biomaterials still remain poorly understood, those candidates have a common feature to promote Nurr1 expression or functions, and part of those candidates have been shown to exert potent antiparkinsonian properties in clinic 64, 68. Further exploration of those modulators should focus on identifying their direct binding regions to Nurr1 and the Nurr1 upstream molecules. All of these efforts may lead to a better understanding of their Nurr1 upregulating mechanisms and discovery of more potent Nurr1‐modulators for the treatment of PD.

Nurr1 Gene Therapy

Recent animal trials of Nurr1 gene therapy have shown a gratifying progress. Two months after midbrain AAV‐Nurr1/Foxa2 injection, the DA neuron density and neurotrophic factor expression are significantly increased in MPTP‐lesioned mice model of PD together with a suppression of proinflammatory cytokine secretion 79. Remarkably, this Nurr1/Foxa2‐mediated cytoprotective effect is observed even 1 year after injection, suggesting that transfection of these genes is an intriguing approach in PD therapy 79. Although the outcome of this trial seems exciting, the safety and feasibility of Nurr1 gene therapy still needs further verification. Firstly, the long‐term effect of constitutive overexpression is not clear. Secondly, this therapeutic strategy has only been tested in toxin‐induced animal models (such as MPTP), but not in transgenic PD models that may mimic a broader pathology of PD. Thirdly, to achieve a better therapeutic outcome, the time window of treatment and a controllable regulation of Nurr1 expression are yet to be further explored.

Interestingly, it has been reported that GDNF which fails to restore DA neuron loss is due to the toxicity of α‐synuclein 32. Considering that the overexpression of Nurr1 may protect DA neurons against α‐synuclein 32, a combinatory delivery of AAV‐Nurr1 with GDNF or neurturin into the midbrain might improve the outcome of the existing preclinical or clinical trials, and predict a very attractive alternative therapy for PD 80.

Prospect of Nurr1‐Based Therapy for PD

Nurr1 serves as a promising target for PD therapy by promoting the survival or genesis of DA neurons 17. As Nurr1 is encoded by an immediate early gene, many modulators are implicated in the Nurr1 pathway. A wide range of physiological signals, such as prostaglandins, fatty acids, calcium, stress, growth factors, inflammatory cytokines, and even physical stimuli, such as membrane depolarization, have been shown to induce Nurr1 expression 81, 82, 83, 84, 85, 86. Besides, aging is a negative factor causing the decline of Nurr1 expression 17, which in turn may reduce the compensatory protective capability of Nurr1 and increase the susceptibility to develop PD. Restoring the impaired Nurr1 functions by Nurr1‐based therapies could provide tentative therapeutic strategies for PD.

RXR, neurotropic factors, cAMP‐responsive element‐binding protein (CREB), and Wnt/β‐catenin pathway seem to play positive roles in regulating Nurr1 expression 87, 88, 89. Thus, we propose that it may be an alternative way to facilitate Nurr1 functions through activating or increasing those modulators. Inspiringly, RXR ligands, such as docosahexaenoic acid, bexarotene, LG100268, and XCT0139508, have been demonstrated to protect DA neurons through interaction with Nurr1/RXR heterodimers 87, 90, 91. Although the biological functions of bexarotene still remain to be defined, one recent study has revealed that bexarotene might have the capacity to rescue the disrupted GDNF signaling and regulate oxidative phosphorylation and Nurr1‐related genes 92. In addition, animal tests have indicated that transplantation of GDNF‐pretreated NSCs could dramatically enhance the expression of Nurr1 and TH 88. Given that GDNF has a poor blood–brain barrier penetrating feature, GDNF inducers, such as telmisartan, calcitriol, rhus verniciflua stokes, and cabergoline, can stimulate GDNF expression 93, 94, 95, 96, 97, 98. Moreover, CREB as an upstream regulator of Nurr1 may play an important role in the process of most modulator‐mediated Nurr1 upregulation, such as prostaglandin E2, thromboxane A2, vascular endothelial growth factor, and N‐methyl‐d‐aspartate 81, 84, 99, 100. Thus, CREB activators or other cAMP increasing agents may also have the capacity to restore Nurr1 functions. However, considering that CREB activates many signal pathways, they in general may not be suitable to treat PD. Furthermore, several studies have indicated that activation of Wnt/β‐catenin signaling pathway could induce the transcription of Nurr1 101, 102, 103. Given that Wnt/β‐catenin pathway is involved in the PD pathogenesis and exogenous Wnt1 could attenuate DA neuron loss in animal models of PD 104, 105, we propose that activating Wnt/β‐catenin pathway, such as GSK‐3β antagonists, may be effective in treating PD through the enhancement of Nurr1 expression 103. Furthermore, Nurr1 activity can be affected by several PD‐related molecules, such as α‐synuclein and microRNA‐132 (miR‐132) 106, 107. Therefore, these molecules may be potential therapeutic targets against PD. Indeed, it has been reported that oligomer selective α‐synuclein antibodies and prolyl oligopeptidase inhibitors are effective in PD models through decelerating the accumulation of α‐synuclein 108, 109, 110. It is plausible that Nurr1 may be involved in the antiparkinsonian effects of those compounds. Moreover, several studies have described a potential role of microRNAs in PD pathogenesis 111, 112, and miR‐132 can directly inhibit Nurr1 expression 107; thus, miR‐132 antagonist may be a potential modulator for PD treatment 107.

Nurr1‐based cell transplantation is another therapy currently under investigation. Several animal experiments have shown the therapeutic potential of Nurr1‐based cell transplantation, not only in ameliorating the behavioral abnormality, but also restoring the DA neuron deficits 113, 114, 115, 116, 117, 118. However, they have not been tested in patients with PD concerning the biosafety and long‐term efficacy of cell transplantation in general 119.

It has been noticed that Nurr1 modulators may have other functions in addition to regulating Nurr1, and most of those compounds have not been evaluated in PD models yet, nor their side effects have been systematically determined. Furthermore, Nurr1 also expresses in nonnervous system 120. Therefore, the nonneurological effects of Nurr1 should not be neglected.

Conclusion

In summary, Nurr1‐activating compounds, Nurr1 modulators, and Nurr1‐based gene therapy have shown their therapeutic potential for PD treatment (as summarized in Figure 1). The pharmacological effects of Nurr1‐based therapies against PD are proposed as follows: (1) increase the expression of DA‐related genes; (2) protect or repair DA neurons against neurotoxins; (3) inhibit the microglia activation and suppress neuroinflammation. These versatile functions make Nurr1 an attracting target for treating PD. Further studies should focus on identifying small molecules, which can effectively activate Nurr1 functions through either direct binding to the specific regions of Nurr1 or modulating the Nurr1‐related signaling. Furthermore, the study of Nurr1 conditional knockout mouse models would be beneficial to better understand the critical roles of Nurr1 in PD pathogenesis, and help screen more specific Nurr1‐activating or Nurr1‐modulating compounds. Although it is still a long way to go for the clinical use in patients with PD, the Nurr1‐based therapies provide a very promising outlook as the next‐generation PD treatment.

Figure 1.

Nurr1 pathway and Nurr1‐based therapies for Parkinson's disease. This figure summarizes the present potential Nurr1‐based therapies, including Nurr1 agonists, gene therapy, and potential regulatory targets of Nurr1 expression. Abbreviations: AF, activation function; cAMP, cyclic adenosine monophosphate; DBD, DNA‐binding domain; FZD, frizzled; GDNF, glial cell line‐derived neurotrophic factor; LBD, ligand‐binding domain; LRP, lipoprotein receptor; microRNA‐132, miR‐132; Ret, proto‐oncogene tyrosine‐protein kinase receptor; RXR, retinoid X receptor; UPS, ubiquitin proteasome system.

Conflict of Interests

The authors confirm that this article content has no conflict of interest.