Increased GSNOR expression during aging impairs cognitive function and decreases S-nitrosation of CaMKIIα
文献类型：期刊论文
| 作者 | Zhang DF5; changchen@moon.ibp.ac.cn; Wang P1,6; Chang C*4,5,7; Liu LM2; Su WT7; Zhang C3; Liu GH6; Yao YG4,5; Yuan ZQ6 |
| 刊名 | Journal of neuroscience
 |
| 出版日期 | 2017 |
| 卷号 | **期号:**页码:Epub ahead of print |
| 英文摘要 | As the population ages, an increasing number of people suffer from age-related cognitive impairment. However, the mechanisms underlying this process remain unclear. Here, we found that S-nitrosoglutathione reductase (GSNOR), the key enzyme that metabolizes intracellular nitric oxide (NO) and regulates S-nitrosation, was significantly increased in the hippocampus of both aging humans and mice. Transgenic mice overexpressing GSNOR exclusively in neurons showed cognitive impairment in behavioral tests, including the Morris water maze, fear conditioning and the Y-maze test. We also found that GSNOR transgenic mice have long-term potentiation (LTP) defects and lower dendrite spine density, while GSNOR knock-out mice rescued the age-related cognitive impairment. Analysis of S-nitrosation showed significantly decreased hippocampal CaMKIIα S-nitrosation in naturally aged mice and GSNOR transgenic mice. Consistent with the change in CaMKIIα S-nitrosation, the accumulation of CaMKIIα in the hippocampal synaptosomal fraction, as well as its downstream signaling targets p (S831)-GLUR1, was also significantly decreased. All these effects could be rescued in the GSNOR knock-out mice. We further verified that the S-nitrosation of CaMKIIα was responsible for the CaMKIIα synaptosomal accumulation by mutating CaMKIIα S-nitrosated sites (C280/289). Up-regulation of the NO signaling pathway rescued the cognitive impairment in GSNOR transgenic mice. In summary, our research demonstrates that GSNOR impairs cognitive function in aging and it could serve as a new potential target for the treatment of age-related cognitive impairment. In contrast to the free radical theory of aging, NO signaling deficiency may be the main mediator of age-related cognitive impairment.SIGNIFICANCE STATEMENTThis study indicated that GSNOR, a key protein S-nitrosation metabolic enzyme, is a new potential target in age-related cognitive impairment and in contrast to the free radical theory of aging, NO signaling deficiency may be the main cause of this process. In addition, increased GSNOR expression during aging decreases S-nitrosation of CaMKIIα and reduces CaMKIIα synaptosomal accumulation. To our knowledge, it is for the first time to show the cellular function regulation of CaMKIIα by GSNOR-dependent S-nitrosation as a new posttranslational modification after its phosphorylation was explored. These findings elucidate a novel mechanism of age-related cognitive impairment and may provide a new potential target and strategy for slowing down this process. |
| 语种 | 英语 |
| 资助机构 | This research was supported by National Key R&D Program of China (2017YFA0504000, 2016YFC0903100 to C.C.), the National Natural Sciences Foundation of China (31500693, 31225012 to C.C.) and Personalized Medicines-Molecular Signature-based Drug Discovery and Development, the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020316 to C.C.) ; This research was supported by National Key R&D Program of China (2017YFA0504000, 2016YFC0903100 to C.C.), the National Natural Sciences Foundation of China (31500693, 31225012 to C.C.) and Personalized Medicines-Molecular Signature-based Drug Discovery and Development, the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020316 to C.C.) ; This research was supported by National Key R&D Program of China (2017YFA0504000, 2016YFC0903100 to C.C.), the National Natural Sciences Foundation of China (31500693, 31225012 to C.C.) and Personalized Medicines-Molecular Signature-based Drug Discovery and Development, the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020316 to C.C.) ; This research was supported by National Key R&D Program of China (2017YFA0504000, 2016YFC0903100 to C.C.), the National Natural Sciences Foundation of China (31500693, 31225012 to C.C.) and Personalized Medicines-Molecular Signature-based Drug Discovery and Development, the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020316 to C.C.) |
| 源URL | [http://159.226.149.26:8080/handle/152453/12039]  |
| 专题 | 昆明动物研究所_动物模型与人类重大疾病机理重点实验室 昆明动物研究所_重大疾病机理的遗传学 |
| 通讯作者 | changchen@moon.ibp.ac.cn |
| 作者单位 | 1.University of Chinese Academy of Sciences, Beijing 100049, China 2.Department of Microbiology and Immunology, University of California 3.School of Life Sciences, Peking University, Beijing 100871, China 4.CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China 5.Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223 China 6.National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China 7.Beijing Institute for Brain Disorders, Capital medical university, Beijing 100069, China |
| 推荐引用方式 GB/T 7714 | Zhang DF,changchen@moon.ibp.ac.cn,Wang P,et al. Increased GSNOR expression during aging impairs cognitive function and decreases S-nitrosation of CaMKIIα[J]. Journal of neuroscience,2017,**(**):Epub ahead of print. |
| APA | Zhang DF.,changchen@moon.ibp.ac.cn.,Wang P.,Chang C*.,Liu LM.,...&Zhang YY.(2017).Increased GSNOR expression during aging impairs cognitive function and decreases S-nitrosation of CaMKIIα.Journal of neuroscience,**(**),Epub ahead of print. |
| MLA | Zhang DF,et al."Increased GSNOR expression during aging impairs cognitive function and decreases S-nitrosation of CaMKIIα".Journal of neuroscience **.**(2017):Epub ahead of print. |
入库方式： OAI收割
来源：昆明动物研究所
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