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J Neurosci. 2017 Oct 4;37(40):9741-9758. doi: 10.1523/JNEUROSCI.0681-17.2017. Epub 2017 Sep 7.

Increased GSNOR Expression during Aging Impairs Cognitive Function and Decreases S-Nitrosation of CaMKIIα.

Zhang Y1,2, Wu K1, Su W3, Zhang DF4, Wang P1,2, Qiao X1,2, Yao Q1,2, Yuan Z1, Yao YG4,5, Liu G1, Zhang C6, Liu L7, Chen C8,2,3.

Author information

1
National Laboratory of Biomacromolecules, Chinese Academy of Sciences Center for Excellence in Biomacromolecules, Institute of Biophysics, Beijing 100101, China.
2
University of Chinese Academy of Sciences, Beijing 100049, China.
3
Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China.
4
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming 650223 China.
5
CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.
6
School of Life Sciences, Peking University, Beijing 100871, China, and.
7
Department of Microbiology and Immunology, University of California, San Francisco, California 94143.
8
National Laboratory of Biomacromolecules, Chinese Academy of Sciences Center for Excellence in Biomacromolecules, Institute of Biophysics, Beijing 100101, China, changchen@moon.ibp.ac.cn.

Abstract

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 LTP defects and lower dendrite spine density, whereas 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/C289). Upregulation 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 STATEMENT This study indicated that S-nitrosoglutathione reductase (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 post-translational 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.

KEYWORDS:

CaMKIIα; S-nitrosation modification; S-nitrosoglutathione reductase; age-related cognitive impairment; nitric oxide

PMID:
28883020
PMCID:
PMC6596611
DOI:
10.1523/JNEUROSCI.0681-17.2017
[Indexed for MEDLINE]
Free PMC Article

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