Article

Aberrant Protein S-Nitrosylation in Neurodegenerative Diseases

Del E. Web Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: .
Neuron (Impact Factor: 15.05). 05/2013; 78(4):596-614. DOI: 10.1016/j.neuron.2013.05.005
Source: PubMed

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.

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    • "Each of the three NOS isoforms have been postulated to play a role in either AD progression or prevention, leading to a seemingly conflicting message about the role of NO in AD and whether NO is neuroprotective or neurotoxic. The signaling pathways of NO converge on three main cellular effects, all of which have been identified to play a role in AD: signaling via soluble guanylate cyclase and the cyclic guanosine monophosphate (cGMP) pathway (Santhanam et al., 2015); direct S-nitrosylation of protein cysteine residues (addition of a nitrosyl ion NO− to generate a nitrosothiol, RS-N=O) (reviewed in (Nakamura et al., 2013)); and protein tyrosine nitration (addition of nitrogen dioxide NO 2 to generate 3-nitrotyrosine) (Hensley et al., 1998). Diversion of NO signaling towards one of these pathways over another depends on the local cellular microenvironment, including levels of transition metal complexes and redox status (Thomas et al., 2002). "
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    • "Therefore, it has to be considered that H 2 S is not working on its own but rather in concert with a host of other reactive chemicals (Hancock & Whiteman, 2014 ). Therefore, similar investigations of thiol modifications needs to be carried out with other compounds, perhaps with other assays too, such as the biotin switch assay (Forrester et al., 2009; Haldar & Stamler, 2013; Nakamura et al., 2013; Zhang et al., 2005), as it is under the physiological conditions in which a protein resides that will determine the exact end result of the thiol alteration. If NO is the predominant signal, then perhaps S-nitrosylation will be the result, but if H 2 O 2 is predominant then the thiol may be oxidized—to varying degrees. "
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    • "S-glutathionylation has both inactivating effects on the function of proteins, but protective effects against irreversible damage of proteins in other condi- tions[161]. Finally, S-nitrosylation of proteins has been related to aging and age-associated neurodegenerative diseases[162]. Succination in age-related disease has not been studied in great detail, but mitochondria are important sites for hydrogen sulfide metabolism and have high sensitivity to hydrogen sulfide signaling[163]. "
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