RT Journal Article
SR Electronic
T1 Increased GSNOR expression during aging impairs cognitive function and decreases S-nitrosation of CaMKIIα
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 0681-17
DO 10.1523/JNEUROSCI.0681-17.2017
A1 Yuying Zhang
A1 Kaiyuan Wu
A1 Wenting Su
A1 Deng-Feng Zhang
A1 Ping Wang
A1 Xinhua Qiao
A1 Qin Yao
A1 Zengqiang Yuan
A1 Yong-Gang Yao
A1 Guanghui Liu
A1 Chen Zhang
A1 Limin Liu
A1 Chen Chang
YR 2017
UL http://www.jneurosci.org/content/early/2017/09/07/JNEUROSCI.0681-17.2017.abstract
AB 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.