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

  • Md. Jakaria
  • Md. Ezazul Haque
  • Duk-Yeon Cho
  • Shofiul Azam
  • In-Su Kim
  • Dong-Kug ChoiEmail author
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.

Keywords

NR4A2 Nuclear receptor Therapeutic target Neuroinflammation Neuronal cell death and neuroprotection 

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

Notes

Availability of Data and Material

Not applicable.

Authors’ 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.

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).

Compliance with Ethical Standards

Competing Interests

The authors declare that they have no competing interests.

Ethics Approval and Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Applied Life Sciences and Integrated Bioscience, Graduate SchoolKonkuk UniversityChungjuSouth Korea
  2. 2.Department of Integrated Bioscience and Biotechnology, College of Biomedical and Health Sciences and Research Institute of Inflammatory Diseases (RID)Konkuk UniversityChungjuSouth Korea

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