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Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN
Zheng, Mei1,2; Liao, Mingxia1; Cui, Tianyuan1; Tian, Honglin3; Fan, Dong-Sheng2; Wan, Qi1
关键词Tar Dna-binding Protein-43 Nr2a-containing Nmda Receptor Pten Glutamate Neurotoxicity Neuroprotection Neurodegeneration
刊名JOURNAL OF CELL SCIENCE
2012-03-15
DOI10.1242/jcs.095729
125期:6页:1556-1567
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Cell Biology
研究领域[WOS]Cell Biology
关键词[WOS]AMYOTROPHIC-LATERAL-SCLEROSIS ; FRONTOTEMPORAL LOBAR DEGENERATION ; LIPID PHOSPHATASE-ACTIVITY ; SPINAL-CORD ; IN-VITRO ; INDUCED EXCITOTOXICITY ; CEREBROSPINAL-FLUID ; DIFFERENTIAL ROLES ; ISCHEMIC TOLERANCE ; NEURONAL INJURY
英文摘要

The dysfunction of TAR DNA-binding protein-43 (TDP-43) is implicated in neurodegenerative diseases. However, the function of TDP-43 is not fully elucidated. Here we show that the protein level of endogenous TDP-43 in the nucleus is increased in mouse cortical neurons in the early stages, but return to basal level in the later stages after glutamate accumulation-induced injury. The elevation of TDP-43 results from a downregulation of phosphatase and tensin homolog (PTEN). We further demonstrate that activation of NR2A-containing NMDA receptors (NR2ARs) leads to PTEN downregulation and subsequent reduction of PTEN import from the cytoplasm to the nucleus after glutamate accumulation. The decrease of PTEN in the nucleus contributes to its reduced association with TDP-43, and thereby mediates the elevation of nuclear TDP-43. We provide evidence that the elevation of nuclear TDP-43, mediated by NR2AR activation and PTEN downregulation, confers protection against cortical neuronal death in the late stages after glutamate accumulation. Thus, this study reveals a NR2AR-PTEN-TDP-43 signaling pathway by which nuclear TDP-43 promotes neuronal survival. These results suggest that upregulation of nuclear TDP-43 represents a self-protection mechanism to delay neurodegeneration in the early stages after glutamate accumulation and that prolonging the upregulation process of nuclear TDP-43 might have therapeutic significance.

语种英语
WOS记录号WOS:000303155400019
项目编号RR024210 ; GM103554
资助机构University of Nevada ; National Center for Research Resources ; National Institute of General Medical Sciences from National Institutes of Health
引用统计
被引频次:20[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/57980
专题北京大学第三临床医学院_神经内科
作者单位1.Univ Nevada, Dept Physiol & Cell Biol, Sch Med, Reno, NV 89557 USA
2.Peking Univ, Dept Neurol, Hosp 3, Beijing 100191, Peoples R China
3.Univ Nevada, Dept Pharmacol, Sch Med, Reno, NV 89557 USA
推荐引用方式
GB/T 7714
Zheng, Mei,Liao, Mingxia,Cui, Tianyuan,et al. Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN[J]. JOURNAL OF CELL SCIENCE,2012,125(6):1556-1567.
APA Zheng, Mei,Liao, Mingxia,Cui, Tianyuan,Tian, Honglin,Fan, Dong-Sheng,&Wan, Qi.(2012).Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN.JOURNAL OF CELL SCIENCE,125(6),1556-1567.
MLA Zheng, Mei,et al."Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN".JOURNAL OF CELL SCIENCE 125.6(2012):1556-1567.
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