Journal
CELL DEATH AND DIFFERENTIATION
Volume 18, Issue 9, Pages 1478-1486Publisher
SPRINGERNATURE
DOI: 10.1038/cdd.2011.65
Keywords
NMDA receptor; S-nitrosylation; misfolded protein; mitochondrial dysfunction; neurodegeneration
Categories
Funding
- NIH [P01 ES016738, P01 HD29587, P30 NS057096, R01 EY05477, R01 EY09024]
- American Parkinson's Disease Association, San Diego Chapter
- Ellison Senior Scholars Award in Aging
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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 Ca2+ 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. Cell Death and Differentiation (2011) 18, 1478-1486; doi:10.1038/cdd.2011.65; published online 20 May 2011
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