title: Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN.
abstract: 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.
authors.affiliation: Department of Neurology, Peking University Third Hospital, 49 North Garden Road, Beijing, 100191,  China.
authors.forename: Mei
authors.initials: M
authors.lastname: Zheng
authors.forename: Mingxia
authors.initials: M
authors.lastname: Liao
authors.forename: Tianyuan
authors.initials: T
authors.lastname: Cui
authors.forename: Honglin
authors.initials: H
authors.lastname: Tian
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Fan
authors.forename: Qi
authors.initials: Q
authors.lastname: Wan
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D057177:TDP-43 Proteinopathies / Q000378:metabolism* / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051059:PTEN Phosphohydrolase; D016194:Receptors, N-Methyl-D-Aspartate; C578077:Tardbp protein, mouse; C487757:Pten protein, mouse