International Journal of Cell Biology 3 Physiological state Pathological state NMDA receptor Ca+2 nNOS NO Protein S-nitrosylation NMDAR Caspase Gospel sGC cGMP cGKI Neuroprotection Synaptic damage Ca+2 nNOS NO Protein S-nitrosylation Protein tyrosine nitration Alteration in mitochondrial dynamics (Cdk5 and Drp1) Protein misfolding stress (PDI) Abberant signal transduction (Cdk5, XIAP) Perturbation in lipid metabolism (ApoE isoforms) Compromise in protein degradation machinery (Parkin) Protein misfolding stress (PDI) Metabolic dysfunction (GAPDH) Compromise in antioxidant capacity (Prx2) Abberant signal transduction (XIAP) Alzheimer,s disease Parkinson,s disease Figure 2: Nitric oxide signaling in neuroprotection and neurodegeneration. Synaptic activity results in NMDAR channel openings, allowing Ca2+ entry that can activate nNOS to generate NO in neurons. Under physiological conditions, low levels of NO are produced in neurons by synaptic activity to activate neuroprotective signaling pathways involving cGMP-CGKI or S-nitrosylation of several critical proteins (NMDARs, Gospel, etc.). Under pathological conditions, excessive Ca2+ enters primarily through extrasynaptic NMDARs, generating large concentrations of NO. The nitrosative stress thus generated contributes to synaptic damage and neuronal loss, in part by fostering aberrant protein S-nitrosylation. Various cellular processes, including mitochondrial dynamics, protein folding, lipid metabolism, protein degradation, and signal transduction pathways can be perturbed by aberrant protein S-nitrosylation. Compromise in one or several of these cell processes can contribute to neurodegeneration. It should be noted, however, that a number of additional pathways, not related to NO, that are triggered by synaptic activity can also contribute to neuroprotection, while a number of pathways aﬀected by extrasynaptic NMDAR activity appear to be involved in neuronal cell injury and death [99]. covalently attached to a cysteine thiol group (or more prop- erly, a thiolate anion, –S−) to form an S-nitroso derivative (R-SNO). Thus, we refer to S-nitrosylated proteins as SNO- proteins. Importantly, not all the cysteines in a protein can be S-nitrosylated. Cysteines that are surrounded by a particular amino-acid motif are likely candidates for this modiﬁcation. This “SNO motif ” is a consensus grouping of amino acids that consists of nucleophilic residues (generally an acid and a base), which may result from protein tertiary or even quaternary structure [24]. A speciﬁc modiﬁcation by S- nitrosylation typically aﬀects protein activity (either activat- ing or inhibiting), thus mediating NO signaling pathways [23, 25, 26]. Proteins also can be denitrosylated (although transnitrosylation may also be involved) reportedly by redox-sensitive enzymes such as the thioredoxin (Trx) and S-nitroso-glutathione reductase systems, protein disulﬁde isomerase (PDI), and alcohol dehydrogenase (ADH) class III, which are now referred to as denitrosylases [27]. 4. Implications of Protein S-Nitrosylation for Neurodegeneration As discussed earlier, NO is produced in normal physiological conditions but does not induce nitrosative stress at low con- centrations. However, under pathological neurodegenerative situations, NO production is highly increased, activating harmful signaling pathways, in large part due to aberrant protein S-nitrosylation. In this section, we will review several of the eﬀects of protein S-nitrosylation in neurodegenerative diseases, including AD and PD. 4.1. Alzheimer’s Disease. AD is one of, if not the most, common forms of dementia, resulting in progressive decline of intellectual and social abilities that cause problems in day- to-day life. AD is a neurodegenerative disorder as there is a tremendous amount of cell injury and loss in various parts of the brain, including the hippocampus and neocortex [28]. One of the important observations in AD pathogenesis is that synaptic deﬁcits precede cellular death and correlate well with decline in intellectual function [29, 30]. Most AD cases (>95%) are sporadic, meaning that the majority of AD onset is not associated with obvious genetic mutations. Since AD mainly occurs in elderly people over 60 years old, age is one of the predisposing factors for the disease. One important hypothesis of aging and diseases of aging is the free radical theory, which states that an organism accumulates oxidative damage over time due to decreases in antioxidant systems and overproduction of free radicals [31, 32]. Consistent with this theory, several studies have clearly shown that AD brains exhibit increased oxidative/nitrosative stress [33]. We have