Abstract
Cell aging depends on the rate of cumulative oxidative and nitrosative damage to DNA and proteins. Accumulated data indicate the involvement of protein S-nitrosylation (SNO), the nitric oxide (NO)-mediated posttranslational modification (PTM) of cysteine thiols, in different brain disorders. However, the changes and involvement of SNO in aging including the development of the organism from juvenile to adult state is still unknown. In this study, using the state-of-the-art mass spectrometry technology to identify S-nitrosylated proteins combined with large-scale computational biology, we tested the S-nitroso-proteome in juvenile and adult mice in both cortical and striatal regions. We found reprogramming of the S-nitroso-proteome in adult mice of both cortex and striatum regions. Significant biological processes and protein–protein clusters associated with synaptic and neuronal terms were enriched in adult mice. Extensive quantitative analysis revealed a large set of potentially pathological proteins that were significantly upregulated in adult mice. Our approach, combined with large scale computational biology allowed us to perform a system-level characterization and identification of the key proteins and biological processes that can serve as drug targets for aging and brain disorders in future studies.
Highlights
Cell aging depends on the rate of cumulative oxidative and nitrosative damage to DNA and proteins
It has been shown that the increase in oxidative/nitrosative stress is accompanied by the mitochondrial dysfunction, increase in superoxide levels, RNA oxidation, NADPH oxidase (NOX) activity, and inducible nitric oxide synthase expression in the hippocampal astrocytes isolated from aged and adult rats[19]
The cortex and striatum, were studied for their well-known role in brain disorders such as ASD, Alzheimer’s disease (AD), Huntington’s disease (HD) and o thers[27,28,29,30,31,32]. This was followed by systems biology analysis combined with bioinformatic to gain the systems-level insight into SNO-proteins’ functionalities, and to test whether enriched processes are changed within age
Summary
Cell aging depends on the rate of cumulative oxidative and nitrosative damage to DNA and proteins. S-nitrosoglutathione reductase (GSNOR) expression has found to be reduced in primary senescent cells during aging in rodents and humans[17] This was accompanied by the increased level of SNO of Dynamin-related protein 1 (Drp1) and Parkin with the downstream effect of the impaired mitophagy, pointing to mitochondrial nitrosative stress[17]. Popa-Wagner et al have recently demonstrated the age-related imbalance in the processes of mitochondrial biogenesis and mitophagy, related to the complexes III and IV of the electron transport chain, that may have a negative impact on the energy production in the cerebellum in old m ice[22] These results can be supported by the data[23] showing that excessive SNO in aging impairs the E3 ubiquitin ligase activity of Parkin, and its ability to act as an enhancer of mitophagy[24,25]. We investigate SNO in aging process and compare for the first time the effects and mechanisms of protein SNO in the brain of the juvenile (6–8 week-old) and adult (3–5 month-old) mice in both cortical and striatal regions
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