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学科主题: 临床医学
题名:
Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN
作者: 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
发表日期: 2012-03-15
DOI: 10.1242/jcs.095729
卷: 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
所属项目编号: RR024210 ; GM103554
项目资助者: University of Nevada ; National Center for Research Resources ; National Institute of General Medical Sciences from National Institutes of Health
WOS记录号: WOS:000303155400019
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/57980
Appears in Collections:北京大学第三临床医学院_神经内科_期刊论文

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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

Recommended Citation:
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.
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