Contra-directional Coupling of Nur77 and Nurr1 in Neurodegeneration: A Novel Mechanism for Memantine-Induced Anti-inflammation and Anti-mitochondrial Impairment.
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.
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600, Guangzhou, Guangdong, 510630, China.
Xiaobo
X
Wei
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600, Guangzhou, Guangdong, 510630, China.
Huimin
H
Gao
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600, Guangzhou, Guangdong, 510630, China.
Jing
J
Zou
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600, Guangzhou, Guangdong, 510630, China.
Xu
X
Liu
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600, Guangzhou, Guangdong, 510630, China.
Dan
D
Chen
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600, Guangzhou, Guangdong, 510630, China.
Jinchi
J
Liao
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600, Guangzhou, Guangdong, 510630, China.
Yunqi
Y
Xu
The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, 410078, China.
Long
L
Ma
The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, 410078, China.
Beisha
B
Tang
The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, 410078, China.
Zhuohua
Z
Zhang
Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, 250# Changgang East Road, Guangzhou, 510260, China.
Xiang
X
Cai
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
K
Jin
Department of Neurosurgery, The University of Texas Medical School at Houston, 6431 Fannin St. MSE R444, Houston, TX, 77030, USA. Ying.Xia@UTH.TMC.edu.
Ying
Y
Xia
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600, Guangzhou, Guangdong, 510630, China. denniswq@yahoo.com.
Qing
Q
Wang
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D055785:Gene Knockdown Techniques; D018698:Glutamic Acid / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008559:Memantine / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology*; D000066829:Neuroprotection / Q000187:drug effects; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000378:metabolism*; D016627:Oxidopamine; D016716:PC12 Cells; D051381:Rats; D013347:Subcellular Fractions / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D050483:Dopamine Plasma Membrane Transport Proteins; D015850:Interleukin-6; C539820:Nr4a1 protein, rat; C539884:Nr4a2 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014409:Tumor Necrosis Factor-alpha; D018698:Glutamic Acid; D016627:Oxidopamine; D045304:Cytochromes c; D007770:L-Lactate Dehydrogenase; D014446:Tyrosine 3-Monooxygenase; D008559:Memantine
Inflammation; Memantine; Neuroprotection; Nur77; Nurr1; Parkinson’s disease