ABSTRACT
Induce Ca2+ Inux ................................................................................................................... 61 6.4 Ca2+ Inux and Generation of Reactive Nitrogen Species/Reactive Oxygen Species ............ 61 6.5 Protein S-Nitrosylation and Neuronal Cell Death .................................................................. 63 6.6 Parkin and the Ubiquitin-Proteasome System ........................................................................64 6.7 S-Nitrosylation and Parkin .....................................................................................................66 6.8 The Unfolded Protein Response and Protein Disulde Isomerase......................................... 67 6.9 S-Nitrosylation of Protein Disulde Isomerase Mediates Protein Misfolding and
Neurotoxicity in Cell Models of Parkinson’s Disease or Alzheimer’s Disease ......................68 6.10 Potential Treatment of Excessive NMDA-Induced Ca2+ Inux and Free Radical
Generation...............................................................................................................................69 6.11 Future Therapeutics: NitroMemantines .................................................................................. 71 6.12 Summary and Conclusions ..................................................................................................... 72 Acknowledgments ............................................................................................................................ 73 References ........................................................................................................................................ 73
Excessive generation of reactive nitrogen species (RNS) and reactive oxygen species (ROS), which lead to neuronal cell injury and death, is a potential mediator of neurodegenerative disorders, including Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), polyglutamine diseases (e.g., Huntington’s disease), glaucoma, human immunodeciency virus-associated dementia, multiple sclerosis, and ischemic brain injury, to name but a few.1-5 While many intra-and extracellular molecules may participate in neuronal injury, accumulation of nitrosative stress due to excessive generation of nitric oxide (NO) appears to be a potential factor contributing to neuronal cell damage and death.6,7 A well-established model for NO production entails a central role of the N-methyl-d-Aspartate (NMDA)-type glutamate receptors in the nervous system. Excessive activation of NMDA receptors (NMDARs) drives Ca2+ inux, which in turn activates neuronal NO synthase (nNOS) and the generation of ROS.8,9 Accumulating evidence suggests that NO can mediate both protective and neurotoxic effects by reacting with cysteine residues of target proteins to form S-nitrosothiols (SNOs), a process termed S-nitrosylation because of its effects on the chemical biology of protein function. Importantly, normal mitochondrial respiration may also generate free radicals, principally ROS, and one such molecule, superoxide anion (O2-), reacts rapidly with free radical NO to form the very toxic product peroxynitrite (ONOO-).10,11
An additional feature of most neurodegenerative diseases is accumulation of misfolded and/ or aggregated proteins.12-15 These protein aggregates can be cytosolic, nuclear, or extracellular. Importantly, protein aggregation can result from either (1) a rare mutation in the disease-related gene encoding the protein or (2) posttranslational changes to the protein engendered by nitrosative/ oxidative stress, which may well account for the more common sporadic cases of the disease.16 A key theme of this article, therefore, is the hypothesis that nitrosative or oxidative stress contributes to protein misfolding in the brains of the majority of neurodegenerative patients. In this review, we discuss specic examples showing that S-nitrosylation of (1) ubiquitin E3 ligases, such as parkin, or (2) endoplasmic reticulum (ER) chaperones, such as protein disulde isomerase (PDI), is critical for the accumulation of misfolded proteins in neurodegenerative diseases such as PD and other conditions.17-20 We also discuss the neuroprotective mechanism of action of NMDA open-channel blockers such as memantine and NO-related drugs for the treatment of neurodegenerative disorders.7,21
Many neurodegenerative diseases are characterized by the accumulation of misfolded proteins that adversely affect neuronal connectivity and plasticity and trigger cell death signaling pathways.12,15 For example, degenerating brain contains aberrant accumulations of misfolded, aggregated proteins, such as α-synuclein and synphilin-1 in PD and amyloid-β (Aβ) and tau in AD. The inclusions observed in PD are called Lewy bodies and are mostly found in the cytoplasm. AD brains show intracellular neurobrillary tangles, which contain tau, and extracellular plaques, which contain Aβ. Other disorders manifesting protein aggregation include Huntington’s disease (polyglutamine), ALS, and prion disease.14 The above-mentioned aggregates may consist of oligomeric complexes of nonnative secondary structures and demonstrate poor solubility in aqueous or detergent solvent.
