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

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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.

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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

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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).

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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.

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Correspondence to Dong-Kug Choi.

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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

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