Article

Redox modulation by S-nitrosylation contributes to protein misfolding, mitochondrial dynamics, and neuronal synaptic damage in neurodegenerative diseases

Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute,10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cell death and differentiation (Impact Factor: 8.18). 05/2011; 18(9):1478-86. DOI: 10.1038/cdd.2011.65
Source: PubMed

ABSTRACT

The pathological processes of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases engender synaptic and neuronal cell damage. While mild oxidative and nitrosative (nitric oxide (NO)-related) stress mediates normal neuronal signaling, excessive accumulation of these free radicals is linked to neuronal cell injury or death. In neurons, N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation and subsequent Ca(2+) influx can induce the generation of NO via neuronal NO synthase. Emerging evidence has demonstrated that S-nitrosylation, representing covalent reaction of an NO group with a critical protein thiol, mediates the vast majority of NO signaling. Analogous to phosphorylation and other posttranslational modifications, S-nitrosylation can regulate the biological activity of many proteins. Here, we discuss recent studies that implicate neuropathogenic roles of S-nitrosylation in protein misfolding, mitochondrial dysfunction, synaptic injury, and eventual neuronal loss. Among a growing number of S-nitrosylated proteins that contribute to disease pathogenesis, in this review we focus on S-nitrosylated protein-disulfide isomerase (forming SNO-PDI) and dynamin-related protein 1 (forming SNO-Drp1). Furthermore, we describe drugs, such as memantine and newer derivatives of this compound that can prevent both hyperactivation of extrasynaptic NMDARs as well as downstream pathways that lead to nitrosative stress, synaptic damage, and neuronal loss.

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    • "This in turn could influence the way oxidized proteins interact with other proteins in the complex cellular milieu. In some cases, posttranslational modifications can lead to protein aggregation and misfolding and act as a trigger of cell death [156] [157]. S-nitrosation of proteins has been recognized as a marker of aging and Alzheimer's disease [158] [159]. "
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    • ", 2013 ) . At the same time the excessive generation of reactive nitrogen species ( RNS ) , including nitric oxide ( NO ) contributes to cell death in neurodegener - ative diseases ( Nakamura and Lipton , 2011 ) . Different stable compounds such as malondialdehyde ( MDA ) and glutathione ; and the activity of antioxidant enzymes such as catalase ( CAT ) and superoxide dismutase ( SOD ) can be used as oxidative stress indicators ( Gonzaíez et al . "
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    • "Pathophysiology is correlated with hypo- or hyper-S-nitrosylation of specific protein targets rather than a general cellular insult due to not only the loss of or enhanced nitric oxide synthase activity but also the denitrosylation by a major denitrosylase, S-nitrosoglutathione reductase (GSNOR) [1]. Abnormal protein S-nitrosylation causes many diseases such as cardiovascular, musculoskeletal, and neurological dysfunction [7]. Furthermore, autophagy, a vacuolar degradation for long-lived and aggregate-prone proteins, plays an important role in neurodegeneration. "
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    ABSTRACT: Arsenic is a class I human carcinogen (such as inducing skin cancer) by its prominent chemical interaction with protein thio (-SH) group. Therefore, arsenic may compromise protein S-nitrosylation by competing the -SH binding activity. In the present study, we aimed to understand the influence of arsenic on protein S-nitrosylation and the following proteomic changes. By using primary human skin keratinocyte, we found that arsenic treatment decreased the level of protein S-nitrosylation. This was coincident to the decent expressions of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS). By using LC-MS/MS, around twenty S-nitrosoproteins were detected in the biotin-switched eluent. With the interest that arsenic not only regulates posttranslational S-nitrosylation but also separately affects protein's translation expression, we performed two-dimensional gel electrophoresis and found that 8 proteins were significantly decreased during arsenic treatment. Whether these decreased proteins are the consequence of protein S-nitrosylation will be further investigated. Taken together, these results provide a finding that arsenic can deplete the binding activity of NO and therefore reduce protein S-nitrosylation.
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