S-Nitrosylation is a redox-mediated posttranslational modification that regulates protein function via covalent reaction of nitric oxide (NO)-related species with a cysteine thiol group on the target ...protein. Under physiological conditions, S-nitrosylation can be an important modulator of signal transduction pathways, akin to phosphorylation. However, with aging or environmental toxins that generate excessive NO, aberrant S-nitrosylation reactions can occur and affect protein misfolding, mitochondrial fragmentation, synaptic function, apoptosis or autophagy. Here, we discuss how aberrantly S-nitrosylated proteins (SNO-proteins) play a crucial role in the pathogenesis of neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. Insight into the pathophysiological role of aberrant S-nitrosylation pathways will enhance our understanding of molecular mechanisms leading to neurodegenerative diseases and point to potential therapeutic interventions.
Increased production of nitric oxide is often associated with age-related neurodegeneration. Here, Nakamura et al. summarize recent findings on protein S-nitrosylation in the brain and propose the concept that aberrant S-nitrosylation reactions contribute to common, sporadic forms of neurodegenerative diseases.
Human induced pluripotent stem cells (hiPSCs) have been generated by reprogramming a number of different somatic cell types using a variety of approaches. In addition, direct reprogramming of mature ...cells from one lineage to another has emerged recently as an alternative strategy for generating cell types of interest. Here we show that a combination of a microRNA (miR-124) and two transcription factors (MYT1L and BRN2) is sufficient to directly reprogram postnatal and adult human primary dermal fibroblasts (mesoderm) to functional neurons (ectoderm) under precisely defined conditions. These human induced neurons (hiNs) exhibit typical neuronal morphology and marker gene expression, fire action potentials, and produce functional synapses between each other. Our findings have major implications for cell-replacement strategies in neurodegenerative diseases, disease modeling, and neural developmental studies.
► miR-124 promotes direct neuronal conversion of human fibroblasts ► Reprogramming of both postnatal and fully adult human fibroblasts ► Robust conversion mediated by a cocktail of miR-124, BRN2, and MYT1L ► Formation of functional synapses between adult human fibroblast-derived neurons
Emerging evidence indicates the importance of S-nitrosation in regulating protein function and activity. This chemical reaction has been termed protein S-nitrosylation to emphasize its biological ...importance as a posttranslational modification, in some ways reminiscent of phosphorylation. The reaction at cysteine thiols is distinct from other chemical reactions of nitric oxide (NO) that activate soluble guanylate cyclase via nitrosylation of heme or formation of peroxynitrite via reaction with superoxide anion to produce tyrosine nitration. Here, we review the importance of pathological, aberrant transnitrosylation reactions, i.e., transfer of the NO group from one protein to another, and its consequent effect on the pathogenesis of neurological disorders, to date on Alzheimer's disease (AD), but also expected to affect Parkinson's disease (PD)/Lewy body dementia (LBD), HIV-associated neurocognitive disorder (HAND), and other neurodegenerative and neurodevelopmental disorders.
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•Aberrant transnitrosylation contributes to neurodegenerative phenotypes, including synaptic loss.•Aberrant transnitrosylation (Uch-L1 to Cdk5 to Drp1) triggers excessive mitochondrial fragmentation in Alzheimer's disease.•Mass spectrometry confirmed the presence of these transnitrosylated proteins in human Alzheimer's disease brains.•Kinetic and thermodynamic considerations favor these aberrant transnitrosylation reactions under disease conditions.•Transnitrosylation-mediated mitochondrial fragmentation results in bioenergetic compromise and synapse loss.
At physiological levels, nitric oxide (NO) contributes to the maintenance of normal neuronal activity and survival, thus serving as an important regulatory mechanism in the central nervous system. By ...contrast, accumulating evidence suggests that exposure to environmental toxins or the normal aging process can trigger excessive production of reactive oxygen/nitrogen species (such as NO), contributing to the etiology of several neurodegenerative diseases. We highlight here protein S -nitrosylation, resulting from covalent attachment of an NO group to a cysteine thiol of the target protein, as a ubiquitous effector of NO signaling in both health and disease. We review our current understanding of this redox-dependent post-translational modification under neurodegenerative conditions, and evaluate how targeting dysregulated protein S -nitrosylation can lead to novel therapeutics.
Neuroprotective drugs tested in clinical trials, particularly those that block N-methyl-D-aspartate-sensitive glutamate receptors (NMDARs), have failed miserably in large part because of intolerable ...side effects. However, one such drug, memantine, was recently approved by the European Union and the US FDA for the treatment of dementia following our group's discovery of its clinically tolerated mechanism of action. Here, we review the molecular basis for memantine efficacy in neurological diseases that are mediated, at least in part, by overactivation of NMDARs, producing excessive Ca(2+) influx through the receptor's associated ion channel and consequent free-radical formation.
Many drugs that have been developed to treat neurodegenerative diseases fail to gain approval for clinical use because they are not well tolerated in humans. In this article, I describe a series of ...strategies for the development of neuroprotective therapeutics that are both effective and well tolerated. These strategies are based on the principle that drugs should be activated by the pathological state that they are intended to inhibit. This approach has already met with success, and has led to the development of the potentially neuroprotective drug memantine, an N-methyl-D-aspartate (NMDA)-type and glutamate receptor antagonist.
Alzheimer's disease (AD) is a devastating disease characterized by synaptic and neuronal loss in the elderly. Compelling evidence suggests that soluble amyloid-β peptide (Aβ) oligomers induce ...synaptic loss in AD. Aβ-induced synaptic dysfunction is dependent on overstimulation of N-methyl-D-aspartate receptors (NMDARs) resulting in aberrant activation of redox-mediated events as well as elevation of cytoplasmic Ca2+, which in turn triggers downstream pathways involving phospho-tau (p-tau), caspases, Cdk5/dynamin-related protein 1 (Drp1), calcineurin/PP2B, PP2A, Gsk-3β, Fyn, cofilin, and CaMKII and causes endocytosis of AMPA receptors (AMPARs) as well as NMDARs. Dysfunction in these pathways leads to mitochondrial dysfunction, bioenergetic compromise and consequent synaptic dysfunction and loss, impaired long-term potentiation (LTP), and cognitive decline. Evidence also suggests that Aβ may, at least in part, mediate these events by causing an aberrant rise in extrasynaptic glutamate levels by inhibiting glutamate uptake or triggering glutamate release from glial cells. Consequent extrasynaptic NMDAR (eNMDAR) overstimulation then results in synaptic dysfunction via the aforementioned pathways. Consistent with this model of Aβ-induced synaptic loss, Aβ synaptic toxicity can be partially ameliorated by the NMDAR antagonists (such as memantine and NitroMemantine). PSD-95, an important scaffolding protein that regulates synaptic distribution and activity of both NMDA and AMPA receptors, is also functionally disrupted by Aβ. PSD-95 dysregulation is likely an important intermediate step in the pathological cascade of events caused by Aβ. In summary, Aβ-induced synaptic dysfunction is a complicated process involving multiple pathways, components and biological events, and their underlying mechanisms, albeit as yet incompletely understood, may offer hope for new therapeutic avenues.
Living cells maintain a balance between oxidation and reduction, and perturbations of this redox balance are thought to contribute to various diseases. Recent attempts to regulate redox state have ...focused on electrophiles (EPs), which activate potent cellular defense systems against oxidative stress. One example of this approach is exemplified by carnosic acid (CA) and carnosol (CS), compounds that are found in the herb rosemary (Rosmarinus officinalis). Importantly, CA and CS themselves are not electrophilic, but in response to oxidation, become electrophilic, and then activate the Keap1/Nrf2/ARE (antioxidant-response element) transcription pathway to synthesize endogenous antioxidant “phase 2” enzymes. As a result of our efforts to develop these compounds as therapeutics for brain health, we have formulated two innovative criteria for drug development: the first concept is the use of pro-electrophilic drugs (PEDs) that are innocuous in and of themselves; and the second concept involves the use of compounds that are pathologically activated therapeutics (PATs);i.e., these small molecules are chemically converted to their active form by the very oxidative stress that they are designed to then combat. The chemical basis for PED and PAT drugs is embodied in the ortho- and para-hydroquinone electrophilic cores of the molecules, which are oxidized by the Cu²⁺/Cu⁺ cycling system (or potentially by other transition metals). Importantly, this cycling pathway is under stringent regulation by the cell redox state. We propose that redox-dependent quinone formation is the predominant mechanism for formation of PED and PAT drugs from their precursor compounds. In fact, redox-dependent generation of the active form of drug from the “pro-form” distinguishes this therapeutic approach from traditional EPs such as curcumin, and results in a decrease in clinical side effects at therapeutic concentrations, e.g., lack of reaction with other thiols such as glutathione (GSH), which can result in lowering GSH and inducing oxidative stress in normal cells. We consider this pro-drug quality of PED/PAT compoundsto be a key factor for generating drugs to be used to combat neurodegenerative diseases that will be clinically tolerated. Given the contribution of oxidative stress to the pathology of multiple neurodegenerative diseases, the Keap1/Nrf2/ARE pathway represents a promising drug target for these PED/PAT agents.
The prevalence of neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), is currently a major public health concern due to the lack of efficient ...disease-modifying therapeutic options. Recent evidence suggests that mitochondrial dysfunction and nitrosative/oxidative stress are key common mediators of pathogenesis. In this review, we highlight molecular mechanisms linking NO-dependent post-translational modifications, such as cysteine S-nitrosylation and tyrosine nitration, to abnormal mitochondrial metabolism. We further discuss the hypothesis that pathological levels of NO compromise brain energy metabolism via aberrant S-nitrosylation of key enzymes in the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, contributing to neurodegenerative conditions. A better understanding of these pathophysiological events may provide a potential pathway for designing novel therapeutics to ameliorate neurodegenerative disorders.
Neurons are particularly sensitive to dysfunction in mitochondrial metabolism due to their high energy demands.
Excessive production of NO-related species is linked to mitochondrial metabolic defects in neurodegenerative diseases.
Aberrant protein S-nitrosylation (producing SNO-proteins) mediates pathological NO signaling cascades, contributing to mitochondrial metabolic dysfunction.
A wide range of aberrantly S-nitrosylated mitochondrial proteins that may contribute to neurodegenerative diseases has been identified; these SNO proteins include enzymes involved in the TCA cycle, the ETC, and mitochondrial dynamics.
Aberrant S-nitrosylation of specific proteins may represent a key mediator of both T2DM/MetS and neurodegenerative disorders such as AD.
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