Aberrant Protein S-Nitrosylation in Neurodegenerative Diseases

Abstract

S-Nitrosylation is a redox-mediated posttranslational modification that regulates protein function via covalent reaction of nitric oxide (NO)-related species with a cysteine thiol group on the target protein. Under physiological conditions, S-nitrosylation can be an important modulator of signal transduction pathways, akin to phosphorylation. However, with aging or environmental toxins that generate excessive NO, aberrant S-nitrosylation reactions can occur and affect protein misfolding, mitochondrial fragmentation, synaptic function, apoptosis or autophagy. Here, we discuss how aberrantly S-nitrosylated proteins (SNO-proteins) play a crucial role in the pathogenesis of neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. Insight into the pathophysiological role of aberrant S-nitrosylation pathways will enhance our understanding of molecular mechanisms leading to neurodegenerative diseases and point to potential therapeutic interventions.

Nitric Oxide Induces Ca2+-independent Activity of the Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII)

“…However, in this case, CaMKII activation by NO did not appear to be through direct S-nitrosylation, as CaMKII activation (and the downstream functions) was instead dependent on PKG (47), which is activated by cGMP after NO-induced guanylyl cyclase activation (17)(18)(19). Notably, however, one of these studies showed that NO donors did also cause a direct 2.5-fold increase of CaMKIIó activity over baseline (46).…”

“…1), and the substitution of one methionine for a cysteine raised the possibility of physiological regulation by nitric oxide (NO)-mediated S-nitrosylation (17)(18)(19), in addition to pathological regulation by oxidation. Such potential CaMKII regulation was intriguing, as nitric oxide (NO) and NO synthase (NOS) are also implicated in hippocampal LTP, LTD, and excitotoxic neuronal cell death (19 -23).…”

S-nitrosylation of fatty acid synthase regulates its activity through dimerization

“…We next investigated whether protein S-nitrosylation, a major posttranslational modifi cation by NO, might have a unique role in adipogenesis. Protein S-nitrosylation can occur even at low levels of NO and can affect the activity and stability of specifi c proteins (36)(37)(38)(39). Immunofl uorescence assay using an antibody against nitroso-cysteine showed that protein S-nitrosylation was higher in differentiated adipocytes (day 9) than in undifferentiated preadipocytes ( Fig.…”

“…Protein S-nitrosylation is a major reversible posttranslational modifi cation by NO that regulates protein function and stability (36)(37)(38)(39)(51)(52)(53)(54)(55)(56). Interestingly, it has been reported that protein S-nitrosylation is increased in adipose tissue in a model of obesity ( 41 ).…”

“…A major mechanism mediating the biological function of NO is protein S-nitrosylation, a posttranslational modifi cation of proteins involving the addition of an NO + to a cysteine thiol group of the proteins. Therefore, under physiological conditions, S-nitrosylation can affect a number of cellular signaling pathways by inducing conformational changes of the protein and affecting protein-protein interactions and protein functions (36)(37)(38)(39). NO is reported to improve the ␤ -oxidation of fatty acids through reversible protein S-nitrosylation ( 40 ).…”