STAT3 ameliorates cognitive deficits by positively regulating the expression of NMDARs in a mouse model of FTDP-17
Abstract In tauopathies, memory impairment positively strongly correlates with the amount of abnormal tau aggregates; however, how tau accumulation induces synapse impairment is unclear. Recently, we found that human tau accumulation activated Signal Transduction and Activator of Transcription-1 (ST...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2020-12-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-020-00290-9 |
| _version_ | 1818387002097139712 |
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| author | Xiao-Yue Hong Hua-Li Wan Ting Li Bing-Ge Zhang Xiao-Guang Li Xin Wang Xiao Li Qian Liu Chong-Yang Chen Ying Yang Qun Wang Shu-Peng Li Hao Yu Jian-Zhi Wang Xi-Fei Yang Gong-Ping Liu |
| author_facet | Xiao-Yue Hong Hua-Li Wan Ting Li Bing-Ge Zhang Xiao-Guang Li Xin Wang Xiao Li Qian Liu Chong-Yang Chen Ying Yang Qun Wang Shu-Peng Li Hao Yu Jian-Zhi Wang Xi-Fei Yang Gong-Ping Liu |
| author_sort | Xiao-Yue Hong |
| collection | DOAJ |
| description | Abstract In tauopathies, memory impairment positively strongly correlates with the amount of abnormal tau aggregates; however, how tau accumulation induces synapse impairment is unclear. Recently, we found that human tau accumulation activated Signal Transduction and Activator of Transcription-1 (STAT1) to inhibit the transcription of synaptic N-methyl-D-aspartate receptors (NMDARs). Here, overexpressing human P301L mutant tau (P301L-hTau) increased the phosphorylated level of Signal Transduction and Activator of Transcription-3 (STAT3) at Tyr705 by JAK2, which would promote STAT3 translocate into the nucleus and activate STAT3. However, STAT3 was found mainly located in the cytoplasm. Further study found that P301L-htau acetylated STAT1 to bind with STAT3 in the cytoplasm, and thus inhibited the nuclear translocation and inactivation of STAT3. Knockdown of STAT3 in STAT3flox/flox mice mimicked P301L-hTau-induced suppression of NMDARs expression, synaptic and memory impairments. Overexpressing STAT3 rescued P301L-hTau-induced synaptic and cognitive deficits by increasing NMDARs expression. Further study proved that STAT3 positively regulated NMDARs transcription through direct binding to the specific GAS element of NMDARs promoters. These findings indicate that accumulated P301L-hTau inactivating STAT3 to suppress NMDARs expression, revealed a novel mechanism for tau-associated synapse and cognition deficits, and STAT3 will hopefully serve as a potential pharmacological target for tauopathies treatment. |
| first_indexed | 2024-12-14T04:03:01Z |
| format | Article |
| id | doaj.art-ad0f6d89ab1645c2844726a407241b48 |
| institution | Directory Open Access Journal |
| issn | 2059-3635 |
| language | English |
| last_indexed | 2024-12-14T04:03:01Z |
| publishDate | 2020-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj.art-ad0f6d89ab1645c2844726a407241b482022-12-21T23:17:54ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352020-12-015111310.1038/s41392-020-00290-9STAT3 ameliorates cognitive deficits by positively regulating the expression of NMDARs in a mouse model of FTDP-17Xiao-Yue Hong0Hua-Li Wan1Ting Li2Bing-Ge Zhang3Xiao-Guang Li4Xin Wang5Xiao Li6Qian Liu7Chong-Yang Chen8Ying Yang9Qun Wang10Shu-Peng Li11Hao Yu12Jian-Zhi Wang13Xi-Fei Yang14Gong-Ping Liu15Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and TechnologyClinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and TechnologyState Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate SchoolBomedical Engineering, Shenzhen PolytechnicDepartment of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and TechnologyKey Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and PreventionDepartment of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and TechnologyAbstract In tauopathies, memory impairment positively strongly correlates with the amount of abnormal tau aggregates; however, how tau accumulation induces synapse impairment is unclear. Recently, we found that human tau accumulation activated Signal Transduction and Activator of Transcription-1 (STAT1) to inhibit the transcription of synaptic N-methyl-D-aspartate receptors (NMDARs). Here, overexpressing human P301L mutant tau (P301L-hTau) increased the phosphorylated level of Signal Transduction and Activator of Transcription-3 (STAT3) at Tyr705 by JAK2, which would promote STAT3 translocate into the nucleus and activate STAT3. However, STAT3 was found mainly located in the cytoplasm. Further study found that P301L-htau acetylated STAT1 to bind with STAT3 in the cytoplasm, and thus inhibited the nuclear translocation and inactivation of STAT3. Knockdown of STAT3 in STAT3flox/flox mice mimicked P301L-hTau-induced suppression of NMDARs expression, synaptic and memory impairments. Overexpressing STAT3 rescued P301L-hTau-induced synaptic and cognitive deficits by increasing NMDARs expression. Further study proved that STAT3 positively regulated NMDARs transcription through direct binding to the specific GAS element of NMDARs promoters. These findings indicate that accumulated P301L-hTau inactivating STAT3 to suppress NMDARs expression, revealed a novel mechanism for tau-associated synapse and cognition deficits, and STAT3 will hopefully serve as a potential pharmacological target for tauopathies treatment.https://doi.org/10.1038/s41392-020-00290-9 |
| spellingShingle | Xiao-Yue Hong Hua-Li Wan Ting Li Bing-Ge Zhang Xiao-Guang Li Xin Wang Xiao Li Qian Liu Chong-Yang Chen Ying Yang Qun Wang Shu-Peng Li Hao Yu Jian-Zhi Wang Xi-Fei Yang Gong-Ping Liu STAT3 ameliorates cognitive deficits by positively regulating the expression of NMDARs in a mouse model of FTDP-17 Signal Transduction and Targeted Therapy |
| title | STAT3 ameliorates cognitive deficits by positively regulating the expression of NMDARs in a mouse model of FTDP-17 |
| title_full | STAT3 ameliorates cognitive deficits by positively regulating the expression of NMDARs in a mouse model of FTDP-17 |
| title_fullStr | STAT3 ameliorates cognitive deficits by positively regulating the expression of NMDARs in a mouse model of FTDP-17 |
| title_full_unstemmed | STAT3 ameliorates cognitive deficits by positively regulating the expression of NMDARs in a mouse model of FTDP-17 |
| title_short | STAT3 ameliorates cognitive deficits by positively regulating the expression of NMDARs in a mouse model of FTDP-17 |
| title_sort | stat3 ameliorates cognitive deficits by positively regulating the expression of nmdars in a mouse model of ftdp 17 |
| url | https://doi.org/10.1038/s41392-020-00290-9 |
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