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

• Main Authors: Tomohiro Nakamura, Olga A. Prikhodko, Elaine Pirie, Saumya Nagar, Mohd Waseem Akhtar, Chang-Ki Oh, Scott R. McKercher, Rajesh Ambasudhan, Shu-ichi Okamoto, Stuart A. Lipton
• Format: Article
• Language: English
• Published: Elsevier 2015-12-01
• Series: Neurobiology of Disease
• Subjects: Nitrosative stress; Nitric oxide; Reactive nitrogen species; S-Nitrosylation; Protein misfolding; Mitochondrial dysfunction
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996115000893

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.