4 found that several proteins critical to neuronal survival are S-nitrosylated and, in some cases, further oxidized in AD, thereby disrupting the normal activity of the protein and contributing to disease pathogenesis, as described below. 4.1.1. S-Nitrosylation of Protein Disulﬁde Isomerase (PDI). Once polypeptides are synthesized on ribosomes, those destined to be secreted are translocated to the endoplasmic reticulum (ER) for proper folding and disulﬁde bond formation. PDI is one of the enzymes that catalyze correct disulﬁde bond formation through a series of thiol-disulﬁde exchange reactions [34, 35]. In the absence of proper disulﬁde bond formation, proteins misfold and aggregate in the ER, resulting in ER stress [36]. If ER stress persists, it can result in cell death [37]. Several lines of research have implicated a role for ER stress in AD pathophysiology [38]. Our laboratory discovered that PDI is S-nitrosylated in human AD brain compared to control brain. S-nitrosylation of PDI facilitates further oxidation of cysteine residues to sulfenic (–SOH), sulﬁnic (–SO2H), and sulfonic (–SO3H) acid PDI derivatives. These redox modiﬁcations compromise PDI chaperone/protein folding function, leading to protein misfolding and ER stress [26]. These results highlighted the role of nitrosative stress and SNO-PDI in neuronal cell injury and death in AD. 4.1.2. S-Nitrosylation of Dynamin Related Protein 1 (Drp1). Neurons, and particularly their synaptic connections, require a tremendous amount of energy due to their high metabolic activity. Mitochondria, being the powerhouses of the cell, generate the vast majority of this energy. Recent reports suggest that to meet energy demand in an eﬃcient manner, mitochondrial dynamics, consisting of ﬁssion and fusion events to generate new mitochondria, have to be carefully regulated [39]. Perturbation of mitochondrial dynamics can have deleterious eﬀects on neuronal function and survival [40, 41]. Studies from our laboratory have shown that aberrant S-nitrosylation of Drp1 (a protein required for mitochondrial ﬁssion) hyperactivates Drp1, and, in turn, causes a dramatic increase in mitochondrial ﬁssion. We demonstrated that the altered mitochondrial dynamics due to S-nitrosylated Drp1 (SNO-Drp1) contributes to synaptic loss in neurons and subsequent neuronal cell death. In addition, SNO-Drp1 levels are signiﬁcantly increased in postmortem sporadic human AD patient brains compared to controls [42]. Hence, this study clearly implicated the patho- physiological role of SNO-Drp1 in AD pathophysiology. 4.1.3. Transnitrosylation of Cdk5 to Drp1. Molecular sig- naling pathways are central to cellular physiology and function. Several signaling molecules have been implicated in AD pathophysiology [43]. One such molecule is cyclin- dependent kinase 5 (Cdk5), the activity of which has been shown to be altered in AD [44]. Cdk5 in neurons does not function as a cell cycle regulator, yet it exerts control over various aspects of neuronal function including cell survival, neuronal migration, dendritic spine density, and synaptic plasticity [45–47]. In a recently published article International Journal of Cell Biology from our laboratory, Qu et al. showed that Cdk5, in addition to being a kinase, is also a nitrosylase, capable of S- nitrosylating other targets involved in both AD and PD. Initially, we found that Cdk5 itself could be S-nitrosylated in an Aβ- and NMDAR-dependant manner in neurons due to generation of NO by these insults [25]. Furthermore, we showed that S-nitrosylation of Cdk5 results in activation and contributes to Aβ-induced dendritic spine loss, representing a decrease in synapses, the only pathological correlate to clinical dementia in AD. Moreover, SNO-Cdk5 levels are signiﬁcantly increased in postmortem sporadic AD patient brains compared to age matched control brains. Importantly, SNO-Cdk5 then appears to contribute to synaptic failure by acting as an endogenous nitrosylase for Drp1, transferring the NO group from Cdk5 to Drp1 to form SNO-Drp1. This study revealed a role for protein S-nitrosylation of Cdk5 in aberrant cell signaling and links this nitrosylase activity to neuronal damage in AD [25]. 4.1.4. S-Nitrosylation of ApoE. Apolipoprotein E (ApoE) represents a major risk factor locus for late onset Alzheimer’s disease [48]. The diﬀerent isoforms of ApoE vary at their cys- teine residues, which are potential sites for S-nitrosylation, as our group had observed a number of years ago. A recent study showed that all ApoE isoforms can bind nNOS and that ApoE2 and ApoE3 can be found in the S-nitrosylated state in human hippocampal lysates [49]. S-Nitrosylation of ApoE isoforms has been suggested to cause loss of binding to low density lipoprotein (LDL) receptors. Thus, S-nitrosylation of ApoE may aﬀect lipid metabolism, which is postulated to aﬀect the progression of AD. The above-mentioned studies highlight some of the roles of S-nitrosylated proteins and how they can alter diverse cellular functions, including mitochondrial dynamics and synapse loss, ER protein folding, signal transduction path- ways, and lipid metabolism, thereby aﬀecting the progression of AD (Figure 2). In addition to these pathways, we suspect that there are many more pathways altered by protein S- nitrosylation in AD pathophysiology. 4.2. Parkinson’s Disease. PD is second only to AD in the prevalence of neurodegenerative disorders. It aﬀects approx- imately 1% of people over 65 years of age [50] and is characterized by motor sequencing impairment and often has a component of dementia. Although there are some symptomatic treatments for patients suﬀering from PD, cur- rently there is no successful therapy to prevent progression or restore function. The histopathological aspects of PD include the loss of dopaminergic neurons, primarily in the substantia nigra pars compacta, often with the simultaneous presence of intracellular inclusions called Lewy bodies. Lewy bodies are mainly distributed in the substantia nigra, neocortex, basal forebrain nuclei, and hippocampus [51, 52]. Despite the fact that some familial cases have been identiﬁed, more than 95% of PD cases are reported as sporadic, some of which appear to be correlated with exposures to agricultural pesticides, herbicides, fungicides, heavy metals, or neurotoxins [53, 54], although this epidemiological information has remained