Because nitric oxide (NO) may be a ubiquitous regulator of cellular signaling, we have modified the yeast two-hybrid system to explore the possibility of NO-dependent protein-protein interactions. We screened for binding partners of procaspase-3, a protein implicated in apoptotic signaling pathways, and identified multiple NO-dependent interactions.Two such interactions, with acid sphingomyelinase and NO synthase, were shown to occur in mammalian cells dependent on endogenous NO. Nitrosylation may thus provide a broad-based mechanism for regulating interactions between proteins. If so, systematic proteomic analyses in which redox state and NO bioavailability are carefully controlled will reveal a large array of novel interactions.
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.
Micronutrients extracted from natural plants or made by biological synthesis are widely used in anti-aging research and applications. Among more than 30 effective anti-aging substances, employing polyphenol organic compounds for modification or delaying of the aging process attracts great interest because of their distinct contribution in the prevention of degenerative diseases, such as cardiovascular disease and cancer. There is a profound potential for polyphenol extracts in the research of aging and the related diseases of the elderly. Previous studies have mainly focused on the properties of polyphenols implicated in free radical scavenging; however, the anti-oxidant effect cannot fully elaborate its biological functions, such as neuroprotection, Aβ protein production, ion channel coupling, and signal transduction pathways. Caenorhabditis elegans (C. elegans) has been considered as an ideal model organism for exploring the mechanism of anti-aging research and is broadly utilized in screening for natural bioactive substances. In this review, we have described the molecular mechanisms and pathways responsible for the slowdown of aging processes exerted by polyphenols. We also have discussed the possible mechanisms for their anti-oxidant and anti-aging properties in C. elegans from the perspective of different classifications of the specific polyphenols, such as flavonols, anthocyanins, flavan-3-ols, hydroxybenzoic acid, hydroxycinnamic acid, and stilbenes.
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