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

Xiaobo Wei, Huimin Gao, Jing Zou, Xu Liu, Dan Chen, Jinchi Liao, Yunqi Xu, Long Ma, Beisha Tang, Zhuohua Zhang, Xiang Cai, Kunling Jin, Ying Xia, Qing Wang

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5876-5892
Number of pages17
JournalMolecular Neurobiology
Volume53
Issue number9
DOIs
StatePublished - 1 Nov 2016

Fingerprint

Memantine
Cytoplasmic and Nuclear Receptors
Oxidopamine
PC12 Cells
Inflammation
Parkinsonian Disorders
Cytosol
Parkinson Disease
Dopaminergic Neurons
Nerve Growth Factor
Post Translational Protein Processing
Up-Regulation
Down-Regulation
Western Blotting
Immunohistochemistry
Neuroprotection

Keywords

  • Inflammation
  • Memantine
  • Neuroprotection
  • Nur77
  • Nurr1
  • Parkinson’s disease

Cite this

Wei, Xiaobo ; Gao, Huimin ; Zou, Jing ; Liu, Xu ; Chen, Dan ; Liao, Jinchi ; Xu, Yunqi ; Ma, Long ; Tang, Beisha ; Zhang, Zhuohua ; Cai, Xiang ; Jin, Kunling ; Xia, Ying ; Wang, Qing. / Contra-directional Coupling of Nur77 and Nurr1 in Neurodegeneration : A Novel Mechanism for Memantine-Induced Anti-inflammation and Anti-mitochondrial Impairment. In: Molecular Neurobiology. 2016 ; Vol. 53, No. 9. pp. 5876-5892.
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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. / Wei, Xiaobo; Gao, Huimin; Zou, Jing; Liu, Xu; Chen, Dan; Liao, Jinchi; Xu, Yunqi; Ma, Long; Tang, Beisha; Zhang, Zhuohua; Cai, Xiang; Jin, Kunling; Xia, Ying; Wang, Qing.

In: Molecular Neurobiology, Vol. 53, No. 9, 01.11.2016, p. 5876-5892.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Contra-directional Coupling of Nur77 and Nurr1 in Neurodegeneration

T2 - A Novel Mechanism for Memantine-Induced Anti-inflammation and Anti-mitochondrial Impairment

AU - Wei, Xiaobo

AU - Gao, Huimin

AU - Zou, Jing

AU - Liu, Xu

AU - Chen, Dan

AU - Liao, Jinchi

AU - Xu, Yunqi

AU - Ma, Long

AU - Tang, Beisha

AU - Zhang, Zhuohua

AU - Cai, Xiang

AU - Jin, Kunling

AU - Xia, Ying

AU - Wang, Qing

PY - 2016/11/1

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N2 - 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.

AB - 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.

KW - Inflammation

KW - Memantine

KW - Neuroprotection

KW - Nur77

KW - Nurr1

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