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

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 transgenic mice have LTP defects and lower dendrite spine density, whereas 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 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 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 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. 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.

Nitrosative stress inhibits aminoacylation and editing activities of mitochondrial threonyl-tRNA synthetase by S-nitrosation

“…S-nitrosation of these protein targets is involved in mitochondrial fission, synaptic dysfunction, protein misfolding and ER stress ( 25 ). Our previous work has also revealed the important role of S-nitrosated modified protein targets, including ATG4B, HDAC2 and CaMKIIα, in neurotoxicity, neuronal differentiation and age-related cognitive impairment ( 28 , 63 , 64 ). S-nitrosation of mitochondrial ThrRS has been shown to transpire naturally in vivo in multiple mouse tissues, including the cortex, liver and heart.…”

Precision Redox: The Key for Antioxidant Pharmacology

“…This not only shows that the redox state is constantly changing throughout the life cycle but also that redox changes are different in different organelles. We have also shown that the expression of GSNOR increases in the aging brain of humans and mice, indicating that the level of NO also changes in these tissues with aging ( 113 ). Interestingly, some studies have found an increase in the total oxidant status (TOS) and total antioxidant capacity (TAC) during labor and delivery in humans ( 65 ) and livestock ( 18 ).…”

eNOS-dependent S-nitrosylation of the NF-κB subunit p65 has neuroprotective effects

“…Moreover, NO was neuroprotective in various animal models of Parkinson Disease, after oxygen-glucose deprivation or cerebral ischemia/reperfusion injury and this effect depended on a reduction in reactive oxygen species and protein S-nitrosylation in brain mitochondria 50 , 51 , while in a pharmacological study, neuroprotection occurred in a PI3K/Akt dependent manner 52 . Interestingly, NO-signaling deficiency may contribute importantly to age-related cognitive impairment 53 . In turn, and in accordance with our data, brain ischemia induced a deleterious elevation of NO and NOS in the hippocampus 54 .…”