Skip to main content
SpringerLink
Log in

Molecular Insights into NR4A2(Nurr1): an Emerging Target for Neuroprotective Therapy Against Neuroinflammation and Neuronal Cell Death

Molecular Neurobiology volume 56, pages 5799–5814 (2019)Cite this article

Abstract

NR4A2 is a nuclear receptor and a transcription factor, with distinctive physiological features. In the cell nuclei of the central nervous system, it is widely expressed and identified as a crucial regulator of dopaminergic (DA) neuronal differentiation, survival, and maintenance. Importantly, it has regulated different genes crucial for dopaminergic signals, and its expression has been diminished in both aged and PD post-mortem brains and reduced in PD patients. In microglia and astrocytes, the expression of NR4A2 has been found where it can be capable of inhibiting the expression of proinflammatory mediators; hence, it protected inflammation-mediated DA neuronal death. In addition, NR4A2 plays neuroprotective role via regulating different signals. However, NR4A2 has been mainly focused on Parkinson’s research, but, in recent times, it has been studied in Alzheimer’s disease (AD), multiple sclerosis (MS), and stroke. Altered expression of NR4A2 is connected to AD progression, and activation of its may improve cognitive function. It is downregulated in peripheral blood mononuclear cells of MS patients; nonetheless, its role in MS has not been fully clear. miR-145-5p known as a putative regulator of NR4A2 and in a middle cerebral artery occlusion/reperfusion model, anti-miR-145-5p administration promoted neurological outcomes in rat. To date, various activators and modulators of NR4A2 have been discovered and investigated as probable therapeutic drugs in neuroinflammatory and neuronal cell death models. The NR4A2 gene and cell-based therapy are described as promising drug candidates for neurodegenerative diseases. Moreover, microRNA might have a crucial role in neurodegeneration via affecting NR4A2 expression. Herein, we present the role of NR4A2 in neuroinflammation and neuronal cell death focusing on neurodegenerative conditions and display NR4A2 as a promising therapeutic target for the therapy of neuroprotection.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Abbreviations

6-OHDA:

6-hydroxyl dopamine

AADC:

L-amino acid decarboxylase

AD:

Alzheimer’s disease

AF-1:

Activation function

CTD:

C-terminal domain

CREB:

cAMP response element-binding protein

DA:

Dopaminergic

DAT:

Dopamine transporter

DBD:

DNA binding domain

DLK1:

Delta-like non-canonical notch ligand 1

GDNF:

Glial cell line-derived neurotrophic factor

GTP:

Guanosine-5′-triphosphate

IL-1β:

Interleukin 1-beta

KLH1:

Keyhole limpet hemocyanin1

LBD:

Ligand-binding domain

MS:

Multiple sclerosis

NTD:

N-terminal domain

NDDs:

Neurodegenerative diseases

NF-κB:

Nuclear factor-kappaB

NGFIB:

Nerve growth factor IB

NR4A1:

Nuclear receptor subfamily 4 group A member 1

NR4A2:

Nuclear receptor subfamily 4 group A member 2

NR4A3:

Nuclear receptor subfamily 4 group A member 1

NSCs:

Neural stem cells

OECs:

Olfactory ensheathing cells

PD:

Parkinson’s disease

PTPRU:

Receptor-type tyrosine-protein phosphatase PCP-2

RXR:

Retinoid X receptor

SN:

Substantia nigra

TH:

Tyrosine hydroxylase

TNF-α:

Tumor necrosis factor-alpha

topo IIβ:

DNA topoisomerase IIβ

VIP:

Vasoactive intestinal peptide

VMAT2:

Vesicular monoamine transporter-2

References

  1. Lallier SW, Graf AE, Waidyarante GR, Rogers LK (2016) Nurr1 expression is modified by inflammation in microglia. Neuroreport 27(15):1120–1127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Beard JA, Tenga A, Hills J, Hoyer JD, Cherian MT, Wang Y-D, Chen T (2016) The orphan nuclear receptor NR4A2 is part of a p53–microRNA-34 network. Sci Rep 6:25108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zetterström RH, Williams R, Perlmann T, Olson L (1996) Cellular expression of the immediate early transcription factors Nurr1 and NGFI-B suggests a gene regulatory role in several brain regions including the nigrostriatal dopamine system. Mol Brain Res 41(1–2):111–120

    Article  PubMed  Google Scholar 

  4. Bäckman C, Perlmann T, Wallén Å, Hoffer BJ, Morales M (1999) A selective group of dopaminergic neurons express Nurr1 in the adult mouse brain. Brain Res 851(1–2):125–132

    Article  PubMed  Google Scholar 

  5. Saucedo-Cardenas O, Conneely OM (1996) Comparative distribution of NURR1 and NUR77 nuclear receptors in the mouse central nervous system. J Mol Neurosci 7(1):51–63

    Article  CAS  PubMed  Google Scholar 

  6. Fan X, Luo G, Ming M, Pu P, Li L, Yang D, Le W (2009) Nurr1 expression and its modulation in microglia. Neuroimmunomodulation 16(3):162–170

    Article  CAS  PubMed  Google Scholar 

  7. Tokuoka H, Hatanaka T, Metzger D, Ichinose H (2014) Nurr1 expression is regulated by voltage-dependent calcium channels and calcineurin in cultured hippocampal neurons. Neurosci Lett 559:50–55

    Article  CAS  PubMed  Google Scholar 

  8. Li T, Yang Z, Li S, Cheng C, Shen B, Le W (2018) Alterations of NURR1 and cytokines in the peripheral blood mononuclear cells: combined biomarkers for Parkinson’s disease. Front Aging Neurosci 29(10):392. https://doi.org/10.3389/fnagi.2018.00392

  9. Tippabathani J, Nellore J, Radhakrishnan V, Banik S, Kapoor S (2017) Identification of NURR1 (exon 4) and FOXA1 (exon 3) haplotypes associated with mRNA expression levels in peripheral blood lymphocytes of Parkinson’s patients in small Indian population. Parkinsons Dis 2017

  10. Moon M, Jeong I, Kim CH, Kim J, Lee PK, Mook-Jung I, Leblanc P, Kim KS (2015) Correlation between orphan nuclear receptor Nurr1 expression and amyloid deposition in 5XFAD mice, an animal model of Alzheimer's disease. J Neurochem 132(2):254–262

    Article  CAS  PubMed  Google Scholar 

  11. Montarolo F, Raffaele C, Perga S, Martire S, Finardi A, Furlan R, Hintermann S, Bertolotto A (2014) Effects of isoxazolo-pyridinone 7e, a potent activator of the Nurr1 signaling pathway, on experimental autoimmune encephalomyelitis in mice. PLoS One 9(9):e108791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rojas P, Joodmardi E, Perlmann T, Ögren SO (2010) Rapid increase of Nurr1 mRNA expression in limbic and cortical brain structures related to coping with depression-like behavior in mice. J Neurosci Res 88(10):2284–2293

    Article  CAS  PubMed  Google Scholar 

  13. Buervenich S, Carmine A, Arvidsson M, Xiang F, Zhang Z, Sydow O, Jönsson EG, Sedvall GC et al (2000) NURR1 mutations in cases of schizophrenia and manic-depressive disorder. Am J Med Genet A 96(6):808–813

    Article  CAS  Google Scholar 

  14. Rojas P, Joodmardi E, Hong Y, Perlmann T, Ögren S (2007) Adult mice with reduced Nurr1 expression: an animal model for schizophrenia. Mol Psychiatry 12(8):756–766

    Article  CAS  PubMed  Google Scholar 

  15. Davies MR, Harding CJ, Raines S, Tolley K, Parker AE, Downey-Jones M, Needham MR (2005) Nurr1 dependent regulation of pro-inflammatory mediators in immortalised synovial fibroblasts. J Inflamm 2(1):15

    Article  CAS  Google Scholar 

  16. Ji L, Gong C, Ge L, Song L, Chen F, Jin C, Zhu H, Zhou G (2017) Orphan nuclear receptor Nurr1 as a potential novel marker for progression in human pancreatic ductal adenocarcinoma. Exp Ther Med 13(2):551–559

    Article  CAS  PubMed  Google Scholar 

  17. Boakye CH, Doddapaneni R, Shah PP, Patel AR, Godugu C, Safe S, Katiyar SK, Singh M (2013) Chemoprevention of skin cancer with 1, 1-bis (3′-indolyl)-1-(aromatic) methane analog through induction of the orphan nuclear receptor, NR4A2 (Nurr1). PLoS One 8(8):e69519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Llopis S, Singleton B, Duplessis T, Carrier L, Rowan B, Williams C (2013) Dichotomous roles for the orphan nuclear receptor NURR1 in breast cancer. BMC Cancer 13(1):139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang J, Yang J, Zou Y, Huang GL, He ZW (2013) Orphan nuclear receptor nurr1 as a potential novel marker for progression in human prostate cancer. Asian Pac J Cancer Prev 14(3):2023–2028

  20. J-i K, Jeon SG, Kim KA, Kim YJ, Song EJ, Choi J, Ahn KJ, Kim C-J et al (2016) The pharmacological stimulation of nurr1 improves cognitive functions via enhancement of adult hippocampal neurogenesis. Stem Cell Res 17(3):534–543

    Article  CAS  Google Scholar 

  21. Smith GA, Rocha EM, Rooney T, Barneoud P, McLean JR, Beagan J, Osborn T, Coimbra M et al (2015) A Nurr1 agonist causes neuroprotection in a Parkinson’s disease lesion model primed with the toll-like receptor 3 dsRNA inflammatory stimulant poly (I: C). PLoS One 10(3):e0121072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chen T (2008) Nuclear receptor drug discovery. Curr Opin Chem Biol 12(4):418–426

    Article  CAS  PubMed  Google Scholar 

  23. Gronemeyer H, Gustafsson J-Å, Laudet V (2004) Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 3(11):950–964

    Article  CAS  PubMed  Google Scholar 

  24. Becnel LB, Darlington YF, Ochsner SA, Easton-Marks JR, Watkins CM, McOwiti A, Kankanamge WH, Wise MW et al (2015) Nuclear receptor signaling atlas: opening access to the biology of nuclear receptor signaling pathways. PLoS One 10(9):e0135615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Maxwell MA, Muscat GE (2006) The NR4A subgroup: immediate early response genes with pleiotropic physiological roles. Nucl Recept Signal 4:nrs.04002

    Article  CAS  Google Scholar 

  26. Ichinose H, Ohye T, Suzuki T, Sumi-Ichinose C, Nomura T, Hagino Y, Nagatsu T (1999) Molecular cloning of the human Nurr1 gene: characterization of the human gene and cDNAs. Gene 230(2):233–239

    Article  CAS  PubMed  Google Scholar 

  27. Paulsen RE, Granås K, Johnsen H, Rolseth V, Sterri S (1995) Three related brain nuclear receptors, NGFI-B, Nurr1, and NOR-1, as transcriptional activators. J Mol Neurosci 6(4):249–255

    Article  CAS  PubMed  Google Scholar 

  28. Maira M, Martens C, Philips A, Drouin J (1999) Heterodimerization between members of the Nur subfamily of orphan nuclear receptors as a novel mechanism for gene activation. Mol Cell Biol 19(11):7549–7557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Perlmann T, Jansson L (1995) A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1. Genes Dev 9(7):769–782

    Article  CAS  PubMed  Google Scholar 

  30. Wang Z, Benoit G, Liu J, Prasad S, Aarnisalo P, Liu X, Xu H, Walker NP et al (2003) Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors. Nature 423(6939):555–560

    Article  CAS  PubMed  Google Scholar 

  31. Maira M, Martens C, Batsché É, Gauthier Y, Drouin J (2003) Dimer-specific potentiation of NGFI-B (Nur77) transcriptional activity by the protein kinase A pathway and AF-1-dependent coactivator recruitment. Mol Cell Biol 23(3):763–776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Codina A, Benoit G, Gooch JT, Neuhaus D, Perlmann T, Schwabe JW (2004) Identification of a novel co-regulator interaction surface on the ligand binding domain of Nurr1 using NMR footprinting. J Biol Chem 279(51):53338–53345

    Article  CAS  PubMed  Google Scholar 

  33. Volakakis N, Malewicz M, Kadkhodai B, Perlmann T, Benoit G (2006) Characterization of the Nurr1 ligand-binding domain co-activator interaction surface. J Mol Endocrinol 37(2):317–326

    Article  CAS  PubMed  Google Scholar 

  34. Kim C-H, Han B-S, Moon J, Kim D-J, Shin J, Rajan S, Nguyen QT, Sohn M et al (2015) Nuclear receptor Nurr1 agonists enhance its dual functions and improve behavioral deficits in an animal model of Parkinson’s disease. Proc Natl Acad Sci 112(28):8756–8761

    Article  CAS  PubMed  Google Scholar 

  35. Zhan Y, Du X, Chen H, Liu J, Zhao B, Huang D, Li G, Xu Q et al (2008) Cytosporone B is an agonist for nuclear orphan receptor Nur77. Nat Chem Biol 4(9):548–556

    Article  CAS  PubMed  Google Scholar 

  36. Chintharlapalli S, Burghardt R, Papineni S, Ramaiah S, Yoon K, Safe S (2005) Activation of Nur77 by selected 1, 1-Bis (3′-indolyl)-1-(p-substituted phenyl) methanes induces apoptosis through nuclear pathways. J Biol Chem 280(26):24903–24914

    Article  CAS  PubMed  Google Scholar 

  37. de Vera IMS, Giri PK, Munoz-Tello P, Brust R, Fuhrmann J, Matta-Camacho E, Shang J, Campbell S et al (2016) Identification of a binding site for unsaturated fatty acids in the orphan nuclear receptor Nurr1. ACS Chem Biol 11(7):1795–1799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Saucedo-Cardenas O, Quintana-Hau JD, Le W-D, Smidt MP, Cox JJ, De Mayo F, Burbach JPH, Conneely OM (1998) Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons. Proc Natl Acad Sci 95(7):4013–4018

    Article  CAS  PubMed  Google Scholar 

  39. Zetterström RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T (1997) Dopamine neuron agenesis in Nurr1-deficient mice. Science 276(5310):248–250

    Article  PubMed  Google Scholar 

  40. Kadkhodaei B, Ito T, Joodmardi E, Mattsson B, Rouillard C, Carta M, Muramatsu S-I, Sumi-Ichinose C et al (2009) Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons. J Neurosci 29(50):15923–15932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Decressac M, Volakakis N, Björklund A, Perlmann T (2013) NURR1 in Parkinson disease—from pathogenesis to therapeutic potential. Nat Rev Neurol 9(11):629–636

    Article  CAS  PubMed  Google Scholar 

  42. Kadkhodaei B, Alvarsson A, Schintu N, Ramsköld D, Volakakis N, Joodmardi E, Yoshitake T, Kehr J et al (2013) Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons. Proc Natl Acad Sci 110(6):2360–2365

    Article  PubMed  Google Scholar 

  43. Heng X, Jin G, Zhang X, Yang D, Zhu M, Fu S, Li X, Le W (2012) Nurr1 regulates top IIβ and functions in axon genesis of mesencephalic dopaminergic neurons. Mol Neurodegener 7(1):4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Eells JB, Misler JA, Nikodem VM (2006) Reduced tyrosine hydroxylase and GTP cyclohydrolase mRNA expression, tyrosine hydroxylase activity, and associated neurochemical alterations in Nurr1-null heterozygous mice. Brain Res Bull 70(2):186–195

    Article  CAS  PubMed  Google Scholar 

  45. Sakurada K, Ohshima-Sakurada M, Palmer TD, Gage FH (1999) Nurr1, an orphan nuclear receptor, is a transcriptional activator of endogenous tyrosine hydroxylase in neural progenitor cells derived from the adult brain. Development 126(18):4017–4026

    CAS  PubMed  Google Scholar 

  46. Sacchetti P, Mitchell TR, Granneman JG, Bannon MJ (2001) Nurr1 enhances transcription of the human dopamine transporter gene through a novel mechanism. J Neurochem 76(5):1565–1572

    Article  CAS  PubMed  Google Scholar 

  47. Hermanson E, Joseph B, Castro D, Lindqvist E, Aarnisalo P, Wallén Å, Benoit G, Hengerer B et al (2003) Nurr1 regulates dopamine synthesis and storage in MN9D dopamine cells. Exp Cell Res 288(2):324–334

    Article  CAS  PubMed  Google Scholar 

  48. Jankovic J, Chen S, Le W (2005) The role of Nurr1 in the development of dopaminergic neurons and Parkinson's disease. Prog Neurobiol 77(1–2):128–138

    Article  CAS  PubMed  Google Scholar 

  49. Chu Y, Kompoliti K, Cochran EJ, Mufson EJ, Kordower JH (2002) Age-related decreases in Nurr1 immunoreactivity in the human substantia nigra. J Comp Neurol 450(3):203–214

    Article  CAS  PubMed  Google Scholar 

  50. Chu Y, Le W, Kompoliti K, Jankovic J, Mufson EJ, Kordower JH (2006) Nurr1 in Parkinson's disease and related disorders. J Comp Neurol 494(3):495–514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Le W-d XP, Jankovic J, Jiang H, Appel SH, Smith RG, Vassilatis DK (2003) Mutations in NR4A2 associated with familial Parkinson disease. Nat Genet 33(1):85

    Article  CAS  Google Scholar 

  52. Le W, Pan T, Huang M, Xu P, Xie W, Zhu W, Zhang X, Deng H et al (2008) Decreased NURR1 gene expression in patients with Parkinson's disease. J Neurol Sci 273(1):29–33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. W-d L, Conneely OM, He Y, Jankovic J, Appel SH (1999) Reduced Nurr1 expression increases the vulnerability of mesencephalic dopamine neurons to MPTP-induced injury. J Neurochem 73:2218–2221

    Google Scholar 

  54. Zhang L, Le W, Xie W, Dani JA (2012) Age-related changes in dopamine signaling in Nurr1 deficient mice as a model of Parkinson's disease. Neurobiology of Aging 33(5):1001. e1007–1001. e1016

    Article  CAS  Google Scholar 

  55. Castelo-Branco G, Wagner J, Rodriguez FJ, Kele J, Sousa K, Rawal N, Pasolli HA, Fuchs E et al (2003) Differential regulation of midbrain dopaminergic neuron development by Wnt-1, Wnt-3a, and Wnt-5a. Proc Natl Acad Sci 100(22):12747–12752

    Article  CAS  PubMed  Google Scholar 

  56. Joksimovic M, Yun BA, Kittappa R, Anderegg AM, Chang WW, Taketo MM, McKay RD, Awatramani RB (2009) Wnt antagonism of Shh facilitates midbrain floor plate neurogenesis. Nat Neurosci 12(2):125–131

    Article  CAS  PubMed  Google Scholar 

  57. Jacobs FM, Van der Linden AJ, Wang Y, von Oerthel L, Sul HS, Burbach JPH, Smidt MP (2009) Identification of Dlk1, Ptpru and Klhl1 as novel Nurr1 target genes in meso-diencephalic dopamine neurons. Development 136(14):2363–2373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Gil M, McKinney C, Lee MK, Eells JB, Phyillaier MA, Nikodem VM (2007) Regulation of GTP cyclohydrolase I expression by orphan receptor Nurr1 in cell culture and in vivo. J Neurochem 101(1):142–150

    Article  CAS  PubMed  Google Scholar 

  59. Luo Y, Henricksen LA, Giuliano RE, Prifti L, Callahan LM, Federoff HJ (2007) VIP is a transcriptional target of Nurr1 in dopaminergic cells. Exp Neurol 203(1):221–232

    Article  CAS  PubMed  Google Scholar 

  60. Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, Gage FH, Glass CK (2009) A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137(1):47–59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. McCoy MK, Martinez TN, Ruhn KA, Szymkowski DE, Smith CG, Botterman BR, Tansey KE, Tansey MG (2006) Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson's disease. J Neurosci 26(37):9365–9375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Long-Smith CM, Collins L, Toulouse A, Sullivan AM, Nolan YM (2010) Interleukin-1β contributes to dopaminergic neuronal death induced by lipopolysaccharide-stimulated rat glia in vitro. J Neuroimmunol 226(1):20–26

    Article  CAS  PubMed  Google Scholar 

  63. Ferrari CC, Godoy MCP, Tarelli R, Chertoff M, Depino AM, Pitossi FJ (2006) Progressive neurodegeneration and motor disabilities induced by chronic expression of IL-1β in the substantia nigra. Neurobiol Dis 24(1):183–193

    Article  CAS  PubMed  Google Scholar 

  64. Liu W, Gao Y, Chang N (2017) 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(4):1312–1319

    Article  CAS  PubMed  Google Scholar 

  65. Dong J, Wang Y, Liu X, Le W (2018) Nurr1 deficiency-mediated inflammatory injury to nigral dopamine neurons in Parkinson’s disease. Parkinsonism Relat Disord 46:e66

    Article  Google Scholar 

  66. Satoh J-I, Nakanishi M, Koike F, Miyake S, Yamamoto T, Kawai M, Kikuchi S, Nomura K et al (2005) Microarray analysis identifies an aberrant expression of apoptosis and DNA damage-regulatory genes in multiple sclerosis. Neurobiol Dis 18(3):537–550

    Article  CAS  PubMed  Google Scholar 

  67. Gilli F, Lindberg RL, Valentino P, Marnetto F, Malucchi S, Sala A, Capobianco M, di Sapio A et al (2010) Learning from nature: pregnancy changes the expression of inflammation-related genes in patients with multiple sclerosis. PLoS One 5(1):e8962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Montarolo F, Perga S, Martire S, Bertolotto A (2015) Nurr1 reduction influences the onset of chronic EAE in mice. Inflamm Res 64(11):841–844

    Article  CAS  PubMed  Google Scholar 

  69. Hara K, Matsukawa N, Yasuhara T, Xu L, Yu G, Maki M, Kawase T, Hess DC et al (2007) Transplantation of post-mitotic human neuroteratocarcinoma-overexpressing Nurr1 cells provides therapeutic benefits in experimental stroke: In vitro evidence of expedited neuronal differentiation and GDNF secretion. J Neurosci Res 85(6):1240–1251

    Article  CAS  PubMed  Google Scholar 

  70. Xie X, Peng L, Zhu J, Zhou Y, Li L, Chen Y, Yu S, Zhao Y (2017) miR-145-5p/Nurr1/TNF-α signaling-induced microglia activation regulates neuron injury of acute cerebral ischemic/reperfusion in rats. Front Mol Neurosci 10

  71. Zu G, Yao J, Ji A, Ning S, Luo F, Li Z, Feng D, Rui Y et al (2017) Nurr1 promotes intestinal regeneration after ischemia/reperfusion injury by inhibiting the expression of p21 (Waf1/Cip1). J Mol Med 95(1):83–95

    Article  CAS  PubMed  Google Scholar 

  72. Merino-Zamorano C, Hernández-Guillamon M, Jullienne A, Le Béhot A, Bardou I, Parés M, Fernández-Cadenas I, Giralt D et al (2014) NURR1 involvement in recombinant tissue-type plasminogen activator treatment complications after ischemic stroke. Stroke. https://doi.org/10.1161/STROKEAHA.114.006826

  73. Zhang T, Jia N, Fei E, Wang P, Liao Z, Ding L, Yan M, Nukina N et al (2007) Nurr1 is phosphorylated by ERK2 in vitro and its phosphorylation upregulates tyrosine hydroxylase expression in SH-SY5Y cells. Neurosci Lett 423(2):118–122

    Article  CAS  PubMed  Google Scholar 

  74. Lu L, Sun X, Liu Y, Zhao H, Zhao S, Yang H (2012) DJ-1 upregulates tyrosine hydroxylase gene expression by activating its transcriptional factor Nurr1 via the ERK1/2 pathway. Int J Biochem Cell Biol 44(1):65–71

    Article  CAS  PubMed  Google Scholar 

  75. Lee MK, Nikodem VM (2004) Differential role of ERK in cAMP-induced Nurr1 expression in N2A and C6 cells. Neuroreport 15(1):99–102

    Article  CAS  PubMed  Google Scholar 

  76. Sim Y, Park G, Eo H, Huh E, Gu PS, Hong S-P, Pak YK, Oh MS (2017) 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

    Article  CAS  PubMed  Google Scholar 

  77. Volpicelli F, Caiazzo M, Greco D, Consales C, Leone L, Perrone-Capano C, D’Amato LC, Ud P (2007) Bdnf gene is a downstream target of Nurr1 transcription factor in rat midbrain neurons in vitro. J Neurochem 102(2):441–453

    Article  CAS  PubMed  Google Scholar 

  78. Barneda-Zahonero B, Servitja J-M, Badiola N, Miñano-Molina AJ, Fadó R, Saura CA, Rodríguez-Alvarez J (2012) Nurr1 protein is required for N-methyl-D-aspartic acid (NMDA) receptor-mediated neuronal survival. J Biol Chem 287(14):11351–11362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Baloh RH, Enomoto H, Johnson EM Jr, Milbrandt J (2000) The GDNF family ligands and receptors—implications for neural development. Curr Opin Neurobiol 10(1):103–110

    Article  CAS  PubMed  Google Scholar 

  80. Alavian KN, Jeddi S, Naghipour SI, Nabili P, Licznerski P, Tierney TS (2014) The lifelong maintenance of mesencephalic dopaminergic neurons by Nurr1 and engrailed. J Biomed Sci 21(1):27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Imam SZ, Jankovic J, Ali SF, Skinner JT, Xie W, Conneely OM, Le W-D (2005) Nitric oxide mediates increased susceptibility to dopaminergic damage in Nurr1 heterozygous mice. FASEB J 19(11):1441–1450

    Article  CAS  PubMed  Google Scholar 

  82. Ji R, Sanchez C, Chou C, Chen X, Woodward D, Regan JW (2012) Prostanoid EP1 receptors mediate up-regulation of the orphan nuclear receptor Nurr1 by cAMP-independent activation of protein kinase A, CREB and NF-κB. Br J Pharmacol 166(3):1033–1046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. de Ortiz SP, Maldonado-Vlaar CS, Carrasquillo Y (2000) Hippocampal expression of the orphan nuclear receptor gene hzf-3/nurr1 during spatial discrimination learning. Neurobiol Learn Mem 74(2):161–178

    Article  CAS  Google Scholar 

  84. Vecsey CG, Hawk JD, Lattal KM, Stein JM, Fabian SA, Attner MA, Cabrera SM, McDonough CB et al (2007) Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB: CBP-dependent transcriptional activation. J Neurosci 27(23):6128–6140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Colón-Cesario WI, Martínez-Montemayor MM, Morales S, Félix J, Cruz J, Adorno M, Pereira L, Colón N et al (2006) Knockdown of Nurr1 in the rat hippocampus: implications to spatial discrimination learning and memory. Learn Mem 13(6):734–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. McQuown SC, Barrett RM, Matheos DP, Post RJ, Rogge GA, Alenghat T, Mullican SE, Jones S et al (2011) HDAC3 is a critical negative regulator of long-term memory formation. J Neurosci 31(2):764–774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hawk JD, Bookout AL, Poplawski SG, Bridi M, Rao AJ, Sulewski ME, Kroener BT, Manglesdorf DJ et al (2012) NR4A nuclear receptors support memory enhancement by histone deacetylase inhibitors. J Clin Invest 122(10):3593–3602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bridi MS, Abel T (2013) The NR4A orphan nuclear receptors mediate transcription-dependent hippocampal synaptic plasticity. Neurobiol Learn Mem 105:151–158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ahn JH, Lee JS, Cho JH, Park JH, Lee TK, Song M, Kim H, Kang SH et al (2018) Age-dependent decrease of Nurr1 protein expression in the gerbil hippocampus. Biomed Rep 8(6):517–522

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Terzioglu-Usak S, Negis Y, S Karabulut D, Zaim M, Isik S (2017) Cellular model of Alzheimer's disease: A&β1-42 peptide induces amyloid deposition and a decrease in topo isomerase II&β and Nurr1 expression. Curr Alzheimer Res 14(6):636–644

    Article  CAS  PubMed  Google Scholar 

  91. Ordentlich P, Yan Y, Zhou S, Heyman RA (2003) Identification of the antineoplastic agent 6-mercaptopurine as an activator of the orphan nuclear hormone receptor Nurr1. J Biol Chem 278(27):24791–24799

    Article  CAS  PubMed  Google Scholar 

  92. Wansa KSA, Harris JM, Yan G, Ordentlich P, Muscat GE (2003) The AF-1 domain of the orphan nuclear receptor NOR-1 mediates trans-activation, coactivator recruitment, and activation by the purine anti-metabolite 6-mercaptopurine. J Biol Chem 278(27):24776–24790

    Article  CAS  PubMed  Google Scholar 

  93. Chang C-Z, Kwan A-L, Howng S-L (2010) 6-Mercaptopurine exerts an immunomodulatory and neuroprotective effect on permanent focal cerebral occlusion in rats. Acta Neurochir 152(8):1383–1390

    Article  PubMed  Google Scholar 

  94. Huang H-Y, Chang H-F, Tsai M-J, Chen J-S, Wang M-J (2016) 6-Mercaptopurine attenuates tumor necrosis factor-α production in microglia through Nur77-mediated transrepression and PI3K/Akt/mTOR signaling-mediated translational regulation. J Neuroinflammation 13(1):78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Van Minh N, Han B-S, Choi H-Y, Byun J, Park J-S, Kim W-G (2017) Genkwalathins A and B, new lathyrane-type diterpenes from Daphne genkwa. Nat Prod Res:1–9

  96. Han B-S, Kim K-S, Kim YJ, Jung H-Y, Kang Y-M, Lee K-S, Sohn M-J, Kim C-H et al (2016) Daphnane diterpenes from Daphne genkwa activate Nurr1 and have a neuroprotective effect in an animal model of Parkinson’s disease. J Nat Prod 79(6):1604–1609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Han B-S, Van Minh N, Choi H-Y, Byun J-S, Kim W-G (2017) Daphnane and phorbol diterpenes, anti-neuroinflammatory compounds with Nurr1 activation from the roots and stems of Daphne genkwa. Biol Pharm Bull 40(12):2205–2211

    Article  CAS  PubMed  Google Scholar 

  98. Hedrick E, Lee S-O, Kim G, Abdelrahim M, Jin U-H, Safe S, Abudayyeh A (2015) Nuclear receptor 4A1 (NR4A1) as a drug target for renal cell adenocarcinoma. PLoS One 10(6):e0128308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Inamoto T, Papineni S, Chintharlapalli S, Cho S-D, Safe S, Kamat AM (2008) 1, 1-Bis (3′-indolyl)-1-(p-chlorophenyl) methane activates the orphan nuclear receptor Nurr1 and inhibits bladder cancer growth. Mol Cancer Ther 7(12):3825–3833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Yoon K, Lee S-O, Cho S-D, Kim K, Khan S, Safe S (2011) Activation of nuclear TR3 (NR4A1) by a diindolylmethane analog induces apoptosis and proapoptotic genes in pancreatic cancer cells and tumors. Carcinogenesis 32(6):836–842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Li X, Lee S-O, Safe S (2012) Structure-dependent activation of NR4A2 (Nurr1) by 1, 1-bis (3′-indolyl)-1-(aromatic) methane analogs in pancreatic cancer cells. Biochem Pharmacol 83(10):1445–1455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. De Miranda BR, Miller JA, Hansen RJ, Lunghofer PJ, Safe S, Gustafson DL, Colagiovanni D, Tjalkens RB (2013) Neuroprotective efficacy and pharmacokinetic behavior of novel anti-inflammatory para-phenyl substituted diindolylmethanes in a mouse model of Parkinson’s disease. J Pharmacol Exp Ther 345(1):125–138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. De Miranda BR, Popichak KA, Hammond SL, Miller JA, Safe S, Tjalkens RB (2014) Novel para-phenyl substituted diindolylmethanes protect against MPTP neurotoxicity and suppress glial activation in a mouse model of Parkinson’s disease. Toxicol Sci 143(2):360–373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. De Miranda BR, Popichak KA, Hammond SL, Jorgensen BA, Phillips AT, Safe S, Tjalkens RB (2015) The Nurr1 activator 1, 1-bis (3′-indolyl)-1-(p-chlorophenyl) methane blocks inflammatory gene expression in BV-2 microglial cells by inhibiting nuclear factor κB. Mol Pharmacol 87(6):1021–1034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Hammond SL, Safe S, Tjalkens RB (2015) A novel synthetic activator of Nurr1 induces dopaminergic gene expression and protects against 6-hydroxydopamine neurotoxicity in vitro. Neurosci Lett 607:83–89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Hammond SL, Popichak KA, Li X, Hunt LG, Richman EH, Damale PU, Chong EK, Backos DS et al (2018) The Nurr1 ligand, 1, 1-bis (3′-Indolyl)-1-(p-Chlorophenyl) methane, modulates glial reactivity and is neuroprotective in MPTP-induced parkinsonism. J Pharmacol Exp Ther 365(3):636–651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Spathis AD, Asvos X, Ziavra D, Karampelas T, Topouzis S, Cournia Z, Qing X, Alexakos P et al (2017) Nurr1: RXRα heterodimer activation as monotherapy for Parkinson’s disease. Proc Natl Acad Sci 114(15):3999–4004

    Article  CAS  PubMed  Google Scholar 

  108. Hintermann S, Chiesi M, Von Krosigk U, Mathe D, Felber R, Hengerer B (2007) Identification of a series of highly potent activators of the Nurr1 signaling pathway. Bioorg Med Chem Lett 17(1):193–196

    Article  CAS  PubMed  Google Scholar 

  109. Zhang Z, Li X, Xie W-j, Tuo H, Hintermann S, Jankovic J, Le W (2012) Anti-parkinsonian effects of Nurr1 activator in ubiquitin-proteasome system impairment induced animal model of Parkinson’s disease. CNS Neurol Disord Drug Targets 11(6):768–773

    Article  CAS  PubMed  Google Scholar 

  110. Wang J, Bi W, Zhao W, Varghese M, Koch RJ, Walker RH, Chandraratna RA, Sanders ME et al (2016) Selective brain penetrable Nurr1 transactivator for treating Parkinson's disease. Oncotarget 7(7):7469–7479

    PubMed  PubMed Central  Google Scholar 

  111. Chandraratna RA, Noelle RJ, Nowak EC (2016) Treatment with retinoid X receptor agonist IRX4204 ameliorates experimental autoimmune encephalomyelitis. Am J Transl Res 8(2):1016–1026

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Qiao S, Tao S, Rojo de la Vega M, Park SL, Vonderfecht AA, Jacobs SL, Zhang DD, Wondrak GT (2013) The antimalarial amodiaquine causes autophagic-lysosomal and proliferative blockade sensitizing human melanoma cells to starvation-and chemotherapy-induced cell death. Autophagy 9(12):2087–2102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Blandini F, Armentero M-T (2014) Dopamine receptor agonists for Parkinson's disease. Expert Opin Investig Drugs 23(3):387–410

    Article  CAS  PubMed  Google Scholar 

  114. Zhang L-M, Sun C-C, Mo M-S, Cen L, Wei L, Luo F-F, Li Y, Li G-F et al (2015) Dopamine agonists exert Nurr1-inducing effect in peripheral blood mononuclear cells of patients with Parkinson's disease. Chin Med J 128(13):1755–1760

    Article  PubMed  PubMed Central  Google Scholar 

  115. Pan T, Xie W, Jankovic J, Le W (2005) Biological effects of pramipexole on dopaminergic neuron-associated genes: relevance to neuroprotection. Neurosci Lett 377(2):106–109

    Article  CAS  PubMed  Google Scholar 

  116. Wei X, Gao H, Zou J, Liu X, Chen D, Liao J, Xu Y, Ma L et al (2016) Contra-directional coupling of Nur77 and Nurr1 in neurodegeneration: a novel mechanism for memantine-induced anti-inflammation and anti-mitochondrial impairment. Mol Neurobiol 53(9):5876–5892

    Article  CAS  PubMed  Google Scholar 

  117. Kiss B, Tóth K, Sarang Z, Garabuczi É, Szondy Z (2015) Retinoids induce Nur77-dependent apoptosis in mouse thymocytes. Biochim Biophys Acta 1853(3):660–670

    Article  CAS  PubMed  Google Scholar 

  118. Li L, Liu Y, H-z C, F-w L, Wu J-f, H-k Z, He J-p, Y-z X et al (2015) Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation. Nat Chem Biol 11(5):339–346

    Article  CAS  PubMed  Google Scholar 

  119. Gervais J, Soghomonian J-J, Richard D, Rouillard C (1999) Dopamine and serotonin interactions in the modulation of the expression of the immediate-early transcription factor, nerve growth factor-inducible B, in the striatum. Neuroscience 91(3):1045–1054

    Article  CAS  PubMed  Google Scholar 

  120. Douxfils J, Buckinx F, Mullier F, Minet V, Rabenda V, Reginster J-Y, Hainaut P, Bruyère O et al (2014) Dabigatran etexilate and risk of myocardial infarction, other cardiovascular events, major bleeding, and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc 3(3):e000515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kandil EA, Sayed RH, Ahmed LA, El Fattah MAA, El-Sayeh BM (2017) Modulatory role of Nurr1 activation and thrombin inhibition in the neuroprotective effects of dabigatran etexilate in rotenone-induced parkinson’s disease in rats. Mol Neurobiol :1–12

  122. Hedya SA, Safar MM, Bahgat AK (2018) Cilostazol mediated Nurr1 and autophagy enhancement: neuroprotective activity in rat rotenone PD model. Mol Neurobiol :1–9

  123. Katsuki H, Kurimoto E, Takemori S, Kurauchi Y, Hisatsune A, Isohama Y, Izumi Y, Kume T et al (2009) Retinoic acid receptor stimulation protects midbrain dopaminergic neurons from inflammatory degeneration via BDNF-mediated signaling. J Neurochem 110(2):707–718

    Article  CAS  Google Scholar 

  124. Esteves M, Cristóvão AC, Saraiva T, Rocha SM, Baltazar G, Ferreira L, Bernardino L (2015) Retinoic acid-loaded polymeric nanoparticles induce neuroprotection in a mouse model for Parkinson's disease. Front Aging Neurosci 7:20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Ham A, Lee HJ, Hong SS, Lee D, Mar W (2012) Moracenin D from Mori cortex Radicis protects SH-SY5Y cells against dopamine-induced cell death by regulating Nurr1 and α-synuclein expression. Phytother Res 26(4):620–624

    Article  CAS  PubMed  Google Scholar 

  126. Shen W, Luo H, Xu L, Wu Z, Chen H, Liu Y, Yu L, Hu L, Wang B, Luo Y et al (2018). Wnt5a mediates the effects of Bushen Huoxue decoction on the migration of bone marrow mesenchymal stem cells in vitro. Chin Med 13:45. https://doi.org/10.1186/s13020-018-0200-2

  127. Pan T, Xie W, Jankovic J, Le W (2005) Radicicol induces heat-shock protein expression and neuroprotection against rotenone-mediated apoptosis in Sh-sy5y cells. Mov Disord 20:S86

    Article  Google Scholar 

  128. Kim H-J, Lee HJ, Jeong S-J, Lee H-J, Kim S-H, Park E-J (2011) Cortex Mori Radicis extract exerts antiasthmatic effects via enhancement of CD4+ CD25+ Foxp3+ regulatory T cells and inhibition of Th2 cytokines in a mouse asthma model. J Ethnopharmacol 138(1):40–46

    Article  PubMed  Google Scholar 

  129. Kim JS, You HJ, Kang HY, Ji GE (2012) Enhancement of the tyrosinase inhibitory activity of Mori cortex radicis extract by biotransformation using Leuconostoc paramesenteroides PR. Biosci Biotechnol Biochem 76(8):1425–1430

    Article  CAS  Google Scholar 

  130. Bidon C, Lachuer J, Molgo J, Wierinckx A, De La Porte S, Pignol B, Christen Y, Meloni R et al (2009) The extract of Ginkgo biloba EGb 761 reactivates a juvenile profile in the skeletal muscle of sarcopenic rats by transcriptional reprogramming. PLoS One 4(11):e7998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Huang D-S, Lin H-Y, Lee-Chen G-J, Hsieh-Li H-M, Wu C-H, Lin J-Y (2016) Treatment with a Ginkgo biloba extract, EGb 761, inhibits excitotoxicity in an animal model of spinocerebellar ataxia type 17. Drug Des Devel Ther 10:723

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Chandrasekaran K, Mehrabian Z, Spinnewyn B, Drieu K, Fiskum G (2001) Neuroprotective effects of bilobalide, a component of the Ginkgo biloba extract (EGb 761), in gerbil global brain ischemia. Brain Res 922(2):282–292

    Article  CAS  PubMed  Google Scholar 

  133. Oyama Y, Chikahisa L, Ueha T, Kanemaru K, Noda K (1996) Ginkgo biloba extract protects brain neurons against oxidative stress induced by hydrogen peroxide. Brain Res 712(2):349–352

    Article  CAS  PubMed  Google Scholar 

  134. Bastianetto S, Ramassamy C, Doré S, Christen Y, Poirier J, Quirion R (2000) The ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by β-amyloid. Eur J Neurosci 12(6):1882–1890

    Article  CAS  PubMed  Google Scholar 

  135. Diamond BJ, Shiflett SC, Feiwel N, Matheis RJ, Noskin O, Richards JA, Schoenberger NE (2000) Ginkgo biloba extract: mechanisms and clinical indications. Arch Phys Med Rehabil 81(5):668–678

    CAS  PubMed  Google Scholar 

  136. von Gunten A, Schlaefke S, Überla K (2016) Efficacy of Ginkgo biloba extract EGb 761® in dementia with behavioural and psychological symptoms: a systematic review. World J Biol Psychiatry 17(8):622–633

    Article  Google Scholar 

  137. Chen X, Hong Y, Zheng P (2015) Efficacy and safety of extract of Ginkgo biloba as an adjunct therapy in chronic schizophrenia: a systematic review of randomized, double-blind, placebo-controlled studies with meta-analysis. Psychiatry Res 228(1):121–127

    Article  CAS  PubMed  Google Scholar 

  138. Rojas P, Ruiz-Sanchez E, Rojas C, Ogren SO (2012) Ginkgo biloba extract (EGb 761) modulates the expression of dopamine-related genes in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice. Neuroscience 223:246–257. https://doi.org/10.1016/j.neuroscience.2012.08.004

    Article  CAS  PubMed  Google Scholar 

  139. Ye S, Gu Y, Xu Y, Fan W, Wang X, Chen S, Cai S, Lv S et al (2014) Bushen Huoxue decoction improves cognitive decline in rats with cerebral hypoperfusion. Mol Med Rep 10(3):1635–1641

    Article  CAS  PubMed  Google Scholar 

  140. Wang H, Yang M, Dou Y, Liu Y, Li S, Li M (2011) Effect of Bushen Huoxue decoction on dopamine D2 receptor in the brain of rats with Parkinson's disease. Nan Fang Yi Ke Da Xue Xue Bao 31(11):1879–1881

    PubMed  Google Scholar 

  141. Yang M-h, Wang H-m, Liu Y (2011) Effect of Bushen Huoxue decoction (补肾活血饮) on the orphan receptor and tyrosine hydroxylase in the brain of rats with Parkinson’s disease. Chin J Integr Med 17(1):43–47

    Article  CAS  PubMed  Google Scholar 

  142. O’Connor DM, Boulis NM (2015) Gene therapy for neurodegenerative diseases. Trends Mol Med 21(8):504–512

    Article  CAS  PubMed  Google Scholar 

  143. Piguet F, Alves S, Cartier N (2017) Clinical gene therapy for neurodegenerative diseases: past, present, and future. Hum Gene Ther 28(11):988–1003

    Article  CAS  PubMed  Google Scholar 

  144. Paliga D, Raudzus F, Leppla SH, Heumann R, Neumann S (2018) Lethal factor domain-mediated delivery of Nurr1 transcription factor enhances tyrosine hydroxylase activity and protects from neurotoxin-induced degeneration of dopaminergic cells. Mol Neurobiol :1–11

  145. Oh SM, Chang MY, Song JJ, Rhee YH, Joe EH, Lee HS, Yi SH, Lee SH (2015) Combined Nurr1 and Foxa2 roles in the therapy of Parkinson's disease. EMBO Molecular Medicine: e201404610

  146. Kim T, Song J-J, Puspita L, Valiulahi P, Shim J-W, Lee S-H (2017) In vitro generation of mature midbrain-type dopamine neurons by adjusting exogenous Nurr1 and Foxa2 expressions to their physiologic patterns. Exp Mol Med 49(3):e300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Decressac M, Kadkhodaei B, Mattsson B, Laguna A, Perlmann T, Björklund A (2012) α-Synuclein-induced down-regulation of Nurr1 disrupts GDNF signaling in nigral dopamine neurons. Sci Transl Med 4(163):163ra156

    Article  CAS  PubMed  Google Scholar 

  148. Bartus RT, Baumann TL, Siffert J, Herzog CD, Alterman R, Boulis N, Turner DA, Stacy M et al (2013) Safety/feasibility of targeting the substantia nigra with AAV2-neurturin in Parkinson patients. Neurology 80(18):1698–1701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Kim J-H, Auerbach JM, Rodríguez-Gómez JA, Velasco I, Gavin D, Lumelsky N, Lee S-H, Nguyen J et al (2002) Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Nature 418(6893):50–56

    Article  CAS  PubMed  Google Scholar 

  150. Wang X, Zhuang W, Fu W, Wang X, Lv E, Li F, Zhou S, Rausch W-D et al (2018) The lentiviral-mediated Nurr1 genetic engineering mesenchymal stem cells protect dopaminergic neurons in a rat model of Parkinson’s disease. Am J Transl Res 10(6):1583–1599

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Yang K-L, Chen M-F, Liao C-H, Pang C-Y, Lin P-Y (2009) A simple and efficient method for generating Nurr1-positive neuronal stem cells from human wisdom teeth (tNSC) and the potential of tNSC for stroke therapy. Cytotherapy 11(5):606–617

    Article  CAS  PubMed  Google Scholar 

  152. Chen X, Qian Y, Wang X, Tang Z, Xu J, Lin H, Yang Z, Song X et al (2018) 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Liu Q, Qin Q, Sun H, Zhong D, An R, Tian Y, Chen H, Jin J, Wang H, Li G (2017) Neuroprotective effect of olfactory ensheathing cells co-transfected with Nurr1 and Ngn2 in both in vitro and in vivo models of Parkinson's disease. Life Sci

  154. Wu S, Sun H, Zhang Q, Jiang Y, Fang T, Cui I, Yan G, Hu Y (2015) MicroRNA-132 promotes estradiol synthesis in ovarian granulosa cells via translational repression of Nurr1. Reprod Biol Endocrinol 13(1):94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Yang D, Li T, Wang Y, Tang Y, Cui H, Tang Y, Zhang X, Chen D et al (2012) miR-132 regulates the differentiation of dopamine neurons by directly targeting Nurr1 expression. J Cell Sci. https://doi.org/10.1242/jcs.086421

  156. Lungu G, Stoica G, Ambrus A (2013) MicroRNA profiling and the role of microRNA-132 in neurodegeneration using a rat model. Neurosci Lett 553:153–158

    Article  CAS  PubMed  Google Scholar 

  157. Yue P, Gao L, Wang X, Ding X, Teng J (2018) Ultrasound-triggered effects of the microbubbles coupled to GDNF-and Nurr1-loaded PEGylated liposomes in a rat model of Parkinson's disease. J Cell Biochem 119(6):4581–4591

    Article  CAS  PubMed  Google Scholar 

Download references

Availability of Data and Material

Not applicable.

Funding

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (NRF-2017R1A2A2A07001035).

Author information

Authors and Affiliations

  1. Department of Applied Life Sciences and Integrated Bioscience, Graduate School, Konkuk University, Chungju, South Korea

    Md. Jakaria, Md. Ezazul Haque, Duk-Yeon Cho, Shofiul Azam, In-Su Kim & Dong-Kug Choi

  2. Department of Integrated Bioscience and Biotechnology, College of Biomedical and Health Sciences and Research Institute of Inflammatory Diseases (RID), Konkuk University, Chungju, South Korea

    In-Su Kim & Dong-Kug Choi

Authors
  1. Md. Jakaria
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Md. Ezazul Haque
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Duk-Yeon Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shofiul Azam
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. In-Su Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dong-Kug Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MJ, I-SK, and D-KC conceived and designed the study. MJ performed the literature review, wrote the manuscript, and compiled the table. MJ and I-SK also produced the figures, and MEH, SA, and D-YC performed the literature review and data arrangement. D-KC also supervised and handled the correspondence. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Dong-Kug Choi.

Ethics declarations

Competing Interests

The authors declare that they have no competing interests.

Ethics Approval and Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jakaria, M., Haque, M.E., Cho, DY. et al. Molecular Insights into NR4A2(Nurr1): an Emerging Target for Neuroprotective Therapy Against Neuroinflammation and Neuronal Cell Death. Mol Neurobiol 56, 5799–5814 (2019). https://doi.org/10.1007/s12035-019-1487-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-019-1487-4

Keywords

search

Navigation