International Journal of Cell Biology contentious in some circles. We and others have shown that several of these environmental factors induce the generation of potentially toxic ROS/RNS species within neuronal cells [55]. Interestingly, dopaminergic neurons are especially vul- nerable to oxidative/nitrosative stress, perhaps partly because of the oxidizing nature of dopamine. These observations have raised the hypothesis that in sporadic PD cases, oxidative or nitrosative stress contributes to PD pathogenesis via altering the function of PD-associated proteins. In several cases, the same gene product that is encoded in hereditary cases of PD may be aﬀected by environmental factors to mimic the more rare genetic form or increase the susceptibility or severity of the hereditary phenotype, as highlighted below. 4.2.1. S-Nitrosylation of Parkin. As an example, mutations in the parkin gene are known to cause many cases of the autosomal-recessive juvenile Parkinsonism and some rare cases of adult-onset PD [56–59]. The parkin gene encodes an ubiquitin E3 ligase that targets many proteins for proteasomal degradation and also has a neuroprotective role in PD-related apoptotic events [56, 60]. Mutations in the parkin gene result in the disturbances in parkin- mediated protein ubiquitination [61–63], which leads to the accumulation of potentially neurotoxic protein aggregates of parkin substrates with consequent dysfunction of the ubiquitin-proteasome system degradative pathway [61, 64, 65]. Interestingly, recent reports suggest that, independently from its ubiquitin-ligase role, parkin also functions as a transcriptional repressor of p53 to protect dopaminergic neurons from PD-related stress [66, 67]. In addition to these rare mutations, several environ- mental toxins that trigger oxidative/nitrosative stress are believed to aﬀect the enzymatic activity of parkin protein. For instance, certain pesticides, herbicides, and fungicides that generate ROS and RNS and have been linked epidemi- ologically to PD can cause alterations in parkin solubility, inducing its aggregation and compromising its protective function. Parkin has multiple cysteine residues in its RING domain and elsewhere [66, 68], which can react with NO to form SNO-parkin. This S-nitrosylation reaction compro- mises parkin’s neuroprotective function. Our group reported that S-nitrosylation of parkin initially increases E3 ligase activity, but with additional time this activity is inhibited. This dysfunctional E3 ligase activity is associated with abnormal protein aggregation resembling Lewy bodies, thus contributing to the parkinsonian phenotype [68]. Moreover, S-nitrosylation of parkin has also been found by our group and others in a mouse MPTP model of PD and in brains of human patients with Lewy body disease (LBD) and PD [68, 69]. These ﬁndings support our notion that posttranslational changes to PD-related proteins via S-nitrosylation or other oxidation reactions may well contribute to the etiology of sporadic PD. 4.2.2. S-Nitrosylation of Peroxiredoxin. Our group and col- leagues have also demonstrated that S-nitrosylation of another protein, peroxiredoxin 2 (Prx2), may be related 5 to PD pathogenesis. Prxs are a highly abundant family of antioxidant enzymes that reduce intracellular peroxides by redox reactions [70–72]. Among the Prx enzymes, Prx2 is the most abundant in the mammalian brain and neurons. The active site cysteine residues in Prx2 reduce peroxides to H2O, thus forming a sulfenic acid (–SOH) derivative of Prx2. Subsequently, the oxidized Prx2 cysteine(s) can either form an intermolecular disulﬁde bond (–S–S–) with another Prx2 molecule, undergo reduction/regeneration back to free sulfhydryl (–SH) by thioredoxin (Trx), or be further oxidized (termed hyperoxidation) to produce a sulﬁnic (–SO2H) or sulfonic (–SO3H) acid derivative. In several neurodegenerative diseases linked to oxida- tive/nitrosative stress, Prx2 levels are increased [73, 74], which may represent an attempt of the cell to counteract oxidative/nitrosative insult during neurodegeneration. We and others recently reported that Prx2 activity can be regulated in vitro and in cell-based systems by NO through S- nitrosylation of redox-active cysteine residues, which would prevent the reaction of this protein with peroxides, thus preventing the neuroprotective action of Prx2 [75, 76]. In human samples of PD brains and cell-based models of PD, S-nitrosylation of Prx2 has been found to be increased compared to control samples [75]. Since SNO-Prx2 cannot react with peroxide because the active cysteines are already nitrosylated, the normal redox cycle to detoxify ROS is disrupted, inducing oxidative stress that can contribute to neuronal cell death. 4.2.3. S-Nitrosylation of XIAP. The protein X-linked inhibitor of apoptosis (XIAP) has also been found to be S- nitrosylated in several neurodegenerative disorders, includ- ing Alzheimer’s, Parkinson’s, and Huntington’s diseases (HD), by our laboratory and others. Inhibitors of apoptosis (IAPs) are a family of proteins that regulate cell survival through binding to caspases to repress their catalytic activity [77, 78]. XIAP is the most commonly expressed and the most potent endogenous caspase inhibitor among the IAPs. XIAP has three copies of the baculovirus IAP repeat (BIR) domain and one RING domain at the C terminal. Biochemical and structural studies demonstrated that BIR domains confer the anticaspase activity [79], whereas the RING domain can act as an E3 ubiquitin ligase in the proteasome system [80–84]. Recent studies show a signiﬁcant increase of S-nitro- sylated XIAP in both cell-based and animal models of PD as well as in human brain samples from PD, AD, and HD patients [85, 86]. Our detailed experiments have identiﬁed that the RING domains of XIAP can react with NO by S-nitrosylation [85], although very high, nonphysiological concentrations of NO can also induce S-nitrosylation of the BIR domain [86]. S-Nitrosylation of XIAP at the RING domain inhibits its E3 ligase and antiapoptotic activity. Furthermore, we demonstrated recently that S-nitrosylated caspases can transfer their NO group to XIAP in a process called transnitrosylation. This reaction inhibits XIAP ubiqui- tin E3 ligase activity on caspases, thus eﬀectively enhancing