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Contra-directional Coupling of Nur77 and Nurr1 in Neurodegeneration: A Novel Mechanism for Memantine-Induced Anti-inflammation and Anti-mitochondrial Impairment

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Abstract

Recent evidence suggests that nerve growth factor IB (Nur77) and nuclear receptor related1 (Nurr1) are differentially involved in dopaminergic neurodegeneration. Since memantine has shown clinically relevant efficacy in Parkinson’s disease (PD) and displayed a potent protective effect on dopaminergic neurons in experimental PD models, we asked if it exerts its neuroprotection by regulating Nur77 and Nurr1 signaling. We adopted a well-established in vitro PD model, 6-hydroxydopamine (OHDA)-lesioned PC12 cells, to test our hypothesis. Different concentrations of memantine were incubated with 6-OHDA-lesioned PC12 cells, and Nur77/Nurr1 and their related signaling molecules were examined by Western blot and immunocytochemistry. Nur77-deficient PC12 cells were used to verify the influences of Nur77 on neurodegeneration and memantine-mediated neuroprotection. We found that memantine reversed Nur77 upregulation and restored Nurr1 downregulation in 6-OHDA-lesioned PC12 cells. 6-OHDA incubation caused Nur77 translocation from the nucleus to cytosol and induced co-localization of Cyt c/HSP60/Nur77 in the cytosol. Memantine strongly reduced the sub-cellular translocations of Nur77/Cyt c/HSP60 under 6-OHDA-induced oxidative condition. Knockdown of Nur77 enhanced the viability of PC12 cells exposed to 6-OHDA, while memantine-induced neuroprotection was much less in the cells with Nur77 knockdown than in those without it. We conclude that Nur77 plays a crucial role in modulating mitochondrial impairment and contributes to neurodegeneration under the experimental PD condition. Memantine effectively suppresses such Nur77-mediated neurodegeneration and promotes survival signaling through post-translational modification of Nurr1. Nur77 and Nurr1 present a contra-directionally coupling interaction in memantine-mediated neuroprotection.

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Abbreviations

AD:

Alzheimer’s disease

AKT:

Also known as protein kinase B

Annexin V-FITC:

Annexin V-fluorescein isothiocyanate

ANOVA:

Analysis of variance

BCA:

Bicinchoninic acid

BDNF:

Brain-derived neurotrophic factor

BSA:

Bovine serum albumin

CCK8:

Cell Counting Kit-8

Cyt c:

Cytochrome c

DA:

Dopamine

DAT:

Dopamine transporter

DMEM:

Dulbecco’s modified Eagle’s medium

DNA:

Deoxyribonucleic acid

EDTA:

Ethylene diamine tetraacetic acid

EGTA:

Ethylene glycol tetraacetic acid

ELISA:

Enzyme-linked immunosorbent assay

ERK:

Extracellular regulated protein kinases

FBS:

Fetal bovine serum

HDAC:

Histone deacetylase

HEPES:

N-2-hydroxyethyl piperazine-N0-2-ethanesulfonic acid

HSP60:

Heat shock protein 60

IL-1:

Interleukin-1

IL-6:

Interleukin-6

JNK:

c-Jun N-terminal kinase

KCL:

Potassium chloride

LBD:

Dementia with Lewy bodies

LDH:

Lactate dehydrogenase

MAPK:

Mitogen-activated protein kinases

NaF:

Sodium fluoride

NaCl:

Sodium chloride

NMDA:

N-Methyl-d-aspartate

NMDAR:

N-Methyl-d-aspartate receptor

NR4A1:

Nuclear receptor subfamily 4, group A, member 1

Nur77:

Nerve growth factor IB

Nurr1:

Nuclear receptor related 1 protein

OD:

Optical density

PBS:

Phosphate buffered saline

PC12 cells:

Pheochromocytoma 12 cells

PD:

Parkinson’s disease

PDD:

Parkinson’s disease dementia

PI:

Propidium iodide

PI3K:

Phosphatidylinositol 3 kinase

PVDF:

Polyvinylidene fluoride

RNA:

Ribonucleic acid

RPMI:

Roswell Park Memorial Institute

RQ-PCR:

Real-time quantitative-polymerase chain reaction

RT-PCR:

Reverse transcription-polymerase chain reaction

SDS:

Sodium dodecyl sulfate

SDS-PAGE:

Sodium dodecyl sulfate-polyacrylamide gel electrophoresis

SEM:

Standard error of the mean

SPSS:

Statistical Product and Service Solutions

TBS:

Tris-buffered saline

TH:

Tyrosine hydroxylase

TNF-α:

Tumor necrosis factor-α

6-OHDA:

6-Hydroxydopamine

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (grant no. 81271427, 81471291), 973 Project (2011CB510000), and Scientific Research Foundation of Guangzhou (grant no. 2014 J4100210), National Natural Science Foundations of Guangdong of China (2014A020212068) to Q.W. Y.X. was partially supported by NIH AT004422 and Vivian L Smith Neurologic Foundation.

Author contributions

X.W., HG, J.Z., Y.X., X.L., and Q.W. conceived and designed the experiments; X.W., H.G., J.Z., Y.X., X.L., J.L., and Q.W. performed the experiments; X.W., J.Z., Y.X., D.C., and Q.W. analyzed the data; Q.W., X.C., L.M., Z.Z., and B.T. contributed reagents/materials/analysis tools; X.C., K.J., Y.X., and Q.W. wrote the paper.

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Competing financial interests: The authors declare no competing financial interests.

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    Authors and Affiliations

    1. Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600, Guangzhou, Guangdong, 510630, China

      Xiaobo Wei, Huimin Gao, Jing Zou, Xu Liu, Dan Chen, Jinchi Liao, Yunqi Xu & Qing Wang

    2. The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, 410078, China

      Long Ma, Beisha Tang & Zhuohua Zhang

    3. Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, 250# Changgang East Road, Guangzhou, 510260, China

      Xiang Cai

    4. Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer’s Disease Research, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA

      Kunling Jin

    5. Department of Neurosurgery, The University of Texas Medical School at Houston, 6431 Fannin St. MSE R444, Houston, TX, 77030, USA

      Ying Xia

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    Xiaobo Wei, Huimin Gao and Jing Zou contributed equally to this work.

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    Wei, X., Gao, H., Zou, J. et al. Contra-directional Coupling of Nur77 and Nurr1 in Neurodegeneration: A Novel Mechanism for Memantine-Induced Anti-inflammation and Anti-mitochondrial Impairment. Mol Neurobiol 53, 5876–5892 (2016). https://doi.org/10.1007/s12035-015-9477-7

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