Hindawi Publishing Corporation International Journal of Cell Biology Volume 2012, Article ID 463756, 9 pages doi:10.1155/2012/463756 Review Article Redox Regulation of Protein Function via Cysteine S-Nitrosylation and Its Relevance to Neurodegenerative Diseases Mohd Waseem Akhtar, Carmen R. Sunico, Tomohiro Nakamura, and Stuart A. Lipton 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 Correspondence should be addressed to Stuart A. Lipton, slipton@sanfordburnham.org Received 13 April 2012; Accepted 17 July 2012 Academic Editor: Pier Giorgio Mastroberardino Copyright © 2012 Mohd Waseem Akhtar et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Debilitating neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), can be attributed to neuronal cell damage in speciﬁc brain regions. An important hallmark of these diseases is increased oxidative and nitrosative stress that occurs via overproduction of highly reactive free radicals known as reactive oxygen species (ROS) and reactive nitrogen species (RNS). These molecules are normally removed by cellular antioxidant systems. Under physiological conditions, ROS/RNS are present at low levels, mediating several neurotrophic and neuroprotective signaling pathways. In contrast, under pathological conditions, there is a pronounced increase in ROS/RNS generation, impairing normal neurological function. Nitric oxide (NO) is one such molecule that functions as a signaling agent under physiological conditions but causes nitrosative stress under pathological conditions due to its enhanced production. As ﬁrst reported by our group and colleagues, the toxic eﬀects of NO can be in part attributed to thiol S-nitrosylation, a posttranslational modiﬁcation of cysteine residues on speciﬁc proteins. Here, we review several reports appearing over the past decade showing that S-nitrosylation of an increasing number of proteins compromises important cellular functions, including mitochondrial dynamics, endoplasmic reticulum (ER) protein folding, and signal transduction, thereby promoting synaptic damage, cell death, and neurodegeneration. 1. Introduction A delicate balance in redox state exists in cells, in large part because of production of ROS/RNS and the antioxidant systems that detoxify them. This homeostatic redox balance maintains a relatively low concentration of ROS/RNS. Under physiological conditions, ROS/RNS can activate speciﬁc signaling pathways required for diverse cellular functions, including cell growth and immune responses [1]. However, increased ROS/RNS production or decreased antioxidant capacity can lead to perturbation of the redox balance, caus- ing oxidative/nitrosative stress [2] (Figure 1). We and oth- ers have demonstrated that sustained oxidative/nitrosative stress elicits counterattack mechanisms, including activation of transcriptional pathways that activate (i) endogenous antioxidant phase 2 enzymes (the Keap1/Nrf2 cascade) and (ii) chaperones for refolding misfolded proteins (heat-shock proteins of the Hsp90/HSF1 cascade). These transcription pathways can be activated directly by ROS/RNS or by electrophilic compounds generated in response to oxidation [3–6]. For example, upon reaction of an electrophile with Keap1, Nrf2 dissociates from the Keap1/Nrf2 complex in the cytoplasm and translocates into the nucleus to initiate transcription of phase 2 antioxidant genes [7–9]. HSF1 acti- vates transcription of heat shock proteins to combat protein misfolding due to stress [10, 11]. If oxidant counteraction mechanisms, including activation of the Keap1/Nrf2 and Hsp90/HSF1 pathways, fail to combat ROS/RNS-related stress, cell injury, and death ensues (Figure 1). Synaptic loss and neuronal cell death due to excessive oxidative/nitrosative stress have been widely implicated in neurodegenerative dis- orders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). ROS and RNS are highly reactive molecules or free radicals. For instance, free radical nitric oxide (NO) possesses an unpaired electron in its outer pi molecular orbital. Due