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Neurobiol Dis. 2015 Dec;84:99-108. doi: 10.1016/j.nbd.2015.03.017. Epub 2015 Mar 18.

Aberrant protein S-nitrosylation contributes to the pathophysiology of neurodegenerative diseases.

Author information

1
Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
2
Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Biomedical Sciences Graduate Program, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
3
Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Graduate School of Biomedical Sciences, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
4
Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Biomedical Sciences Graduate Program, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Neurosciences, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: slipton@ucsd.edu.

Abstract

Nitric oxide (NO) is a gasotransmitter that impacts fundamental aspects of neuronal function in large measure through S-nitrosylation, a redox reaction that occurs on regulatory cysteine thiol groups. For instance, S-nitrosylation regulates enzymatic activity of target proteins via inhibition of active site cysteine residues or via allosteric regulation of protein structure. During normal brain function, protein S-nitrosylation serves as an important cellular mechanism that modulates a diverse array of physiological processes, including transcriptional activity, synaptic plasticity, and neuronal survival. In contrast, emerging evidence suggests that aging and disease-linked environmental risk factors exacerbate nitrosative stress via excessive production of NO. Consequently, aberrant S-nitrosylation occurs and represents a common pathological feature that contributes to the onset and progression of multiple neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases. In the current review, we highlight recent key findings on aberrant protein S-nitrosylation showing that this reaction triggers protein misfolding, mitochondrial dysfunction, transcriptional dysregulation, synaptic damage, and neuronal injury. Specifically, we discuss the pathological consequences of S-nitrosylated parkin, myocyte enhancer factor 2 (MEF2), dynamin-related protein 1 (Drp1), protein disulfide isomerase (PDI), X-linked inhibitor of apoptosis protein (XIAP), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) under neurodegenerative conditions. We also speculate that intervention to prevent these aberrant S-nitrosylation events may produce novel therapeutic agents to combat neurodegenerative diseases.

KEYWORDS:

Mitochondrial dysfunction; Neuronal cell death; Nitric oxide; Nitrosative stress; Protein misfolding; Reactive nitrogen species; S-Nitrosylation; Synaptic injury; Transcriptional dysregulation

PMID:
25796565
PMCID:
PMC4575233
DOI:
10.1016/j.nbd.2015.03.017
[Indexed for MEDLINE]
Free PMC Article

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