Aberrant protein S-nitrosylation contributes to the pathophysiology of neurodegenerative diseases

Nakamura, Tomohiro; Prikhodko, Olga; Pirie, Elaine; Nagar, Saumya; Akhtar, Mohd Waseem; Oh, Chang-ki; McKercher, Scott R.; Ambasudhan, Rajesh; Okamoto, Shu-ichi; Lipton, Stuart A.

doi:10.1016/j.nbd.2015.03.017

Cited by 140 publications

(129 citation statements)

References 115 publications

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“…Currently, the identification of a specific SNO residue involves an iterative combination of mutagenic and mass spectrometry (MS)-based approaches. The prototypical method for detecting SNO-proteins is the biotinswitch technique (BST), which requires blocking of all free Cysthiols, followed by selective ascorbate reduction of SNO-Cys residues that are biotinylated and isolated for analysis (9,(15)(16)(17). One limitation of the BST is that false positives can occur through incomplete blocking of free Cys-thiols, making them difficult to distinguish from true SNO-Cys residues.…”

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confidence: 99%

“…In the healthy brain, low levels of NO and normal SNO PTMs play important roles in regulating synaptic plasticity, gene expression, and neuronal survival. In contrast, elevated NO levels associated with aging and environmental stress have been linked to neurological pathologies, including Alzheimer's (AD), Parkinson's, and Huntington's disease (9). AD is the most prevalent form of human dementia, with a frequency that progressively increases in aging societies (10).…”

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confidence: 99%

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S -nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration

Seneviratne

Nott

Bhat

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Protein S-nitrosation (SNO-protein), the nitric oxide-mediated posttranslational modification of cysteine thiols, is an important regulatory mechanism of protein function in both physiological and pathological pathways. A key first step toward elucidating the mechanism by which S-nitrosation modulates a protein's function is identification of the targeted cysteine residues. Here, we present a strategy for the simultaneous identification of SNO-cysteine sites and their cognate proteins to profile the brain of the CK-p25-inducible mouse model of Alzheimer's disease-like neurodegeneration. The approach-SNOTRAP (SNO trapping by triaryl phosphine)-is a direct tagging strategy that uses phosphine-based chemical probes, allowing enrichment of SNO-peptides and their identification by liquid chromatography tandem mass spectrometry. SNOTRAP identified 313 endogenous SNO-sites in 251 proteins in the mouse brain, of which 135 SNO-proteins were detected only during neurodegeneration. S-nitrosation in the brain shows regional differences and becomes elevated during early stages of neurodegeneration in the CK-p25 mouse. The SNO-proteome during early neurodegeneration identified increased S-nitrosation of proteins important for synapse function, metabolism, and Alzheimer's disease pathology. In the latter case, proteins related to amyloid precursor protein processing and secretion are S-nitrosated, correlating with increased amyloid formation. Sequence analysis of SNO-cysteine sites identified potential linear motifs that are altered under pathological conditions. Collectively, SNOTRAP is a direct tagging tool for global elucidation of the SNO-proteome, providing functional insights of endogenous SNO proteins in the brain and its dysregulation during neurodegeneration.S-nitrosation | Alzheimer's disease | secretase pathway | presenilin pathway | neurodegeneration P rotein S-nitrosation (SNO-protein), in which a cysteine (Cys) thiol is converted to a nitrosothiol (RSNO), is an important posttranslational modification (PTM). Cys residues targeted for S-nitrosation often impact enzyme activity, protein localization, and protein-protein interactions (1). SNO begins with the production of nitric oxide radicals (NO • ) via conversion of L-arginine to L-citrulline by nitric oxide synthase 1 (NOS1) (neuronal), NOS2 (inducible), and NOS3 (endothelial). NO-mediated SNO PTMs are thought to occur in vivo predominantly through radical recombination between NO • and a thiyl radical, transnitrosation by low-molecular weight NO carriers such as S-nitrosoglutathione (GSNO), or protein-assisted transnitrosation (2-8). In the healthy brain, low levels of NO and normal SNO PTMs play important roles in regulating synaptic plasticity, gene expression, and neuronal survival. In contrast, elevated NO levels associated with aging and environmental stress have been linked to neurological pathologies, including Alzheimer's (AD), Parkinson's, and Huntington's disease (9). AD is the most prevalent form of human dementia, with a frequency that progressiv...

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confidence: 99%

mentioning

confidence: 99%

S -nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration

Seneviratne

Nott

Bhat

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Previously, our group and others have shown that aberrant thiol oxidation (protein sulfonation or S-nitrosylation) is implicated in multiple neurodegenerative disorders, contributing to disease etiology and progression (34,51). Oxidation of proteins in general has been reported in retinal degeneration (3,12,14,52).…”

Section: Discussionmentioning

confidence: 98%

“…2 A and B). We and others have shown that excessive ROS production can result in posttranslational modification of protein cysteine thiols, leading to alterations in functional activity (33,34). To determine if these levels of ROS can oxidize MEF2D in a similar manner, we used DCP-Bio1 to probe for sulfenated (-SOH) MEF2D adducts in intact retinas exposed to hydrogen peroxide as a ROS generator.…”

Section: Mef2dmentioning

confidence: 99%

MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress

Nagar

Noveral

Trudler

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Gaining mechanistic insight into interaction between causative factors of complex multifactorial diseases involving photoreceptor damage might aid in devising effective therapies. Oxidative stress is one of the potential unifying mechanisms for interplay between genetic and environmental factors that contribute to photoreceptor pathology. Interestingly, the transcription factor myocyte enhancer factor 2d (MEF2D) is known to be important in photoreceptor survival, as knockout of this transcription factor results in loss of photoreceptors in mice. Here, using a mild light-induced retinal degeneration model, we show that the diminished MEF2D transcriptional activity in Mef2d +/− retina is further reduced under photostimulation-induced oxidative stress. Reactive oxygen species cause an aberrant redox modification on MEF2D, consequently inhibiting transcription of its downstream target, nuclear factor (erythroid-derived 2)-like 2 (NRF2). NRF2 is a master regulator of phase II antiinflammatory and antioxidant gene expression. In the Mef2d heterozygous mouse retina, NRF2 is not up-regulated to a normal degree in the face of lightinduced oxidative stress, contributing to accelerated photoreceptor cell death. Furthermore, to combat this injury, we found that activation of the endogenous NRF2 pathway using proelectrophilic drugs rescues photoreceptors from photo-induced oxidative stress and may therefore represent a viable treatment for oxidative stress-induced photoreceptor degeneration, which is thought to contribute to some forms of retinitis pigmentosa and age-related macular degeneration.B lindness due to photoreceptor loss from a number of diseases is a prevalent and devastating condition in the human population. Genetic predisposition and environmental stress play major roles in the incidence and progression of the retinal degeneration. Understanding disease mechanisms and interactions of causative factors should help in the design of treatment strategies. Recent evidence indicates that oxidative stress, contributing to photoreceptor cell death, plays a significant role in the pathophysiology of nonsyndromic retinitis pigmentosa (RP) and possibly age-related macular degeneration (AMD) (1-3). Moreover, light-induced oxidative stress is known to potentiate photoreceptor loss in genetic models mimicking a number of human retinal degenerations (4-11).The oxidizing microenvironment of the retinal pigment epithelium (RPE)-photoreceptor complex has been predominantly attributed to high oxygen demand, abundant polyunsaturated fatty acids, and direct exposure to light, coupled with the adjacent choroidal hemodynamics (12). Light exposure compounded over many years in the presence of photosensitizers may prime photoreceptors and RPE for free radical/oxidative damage (12-14). In some animal models of photoreceptor degeneration, including RP and Leber congenital amaurosis, disease progression is accelerated by exposure to light and slowed by rearing in darkness (3, 15). Advanced age also compromises the endogenous antioxidant ...

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“…In particular, many lines of evidence indicate that GAPDH functions as a key mediator in apoptotic cell death during neurodegeneration (Chuang & Ishitani 1996), although its molecular mechanism is not understood completely. Given recent findings that GAPDH undergoes S-nitrosylation at the catalytic cysteine residue (Cys152 in human; Cys150 in mouse and rat) by nitric oxide (NO) under pathological conditions, S-nitrosylated GAPDH is thought to contribute to nuclear signaling events leading to apoptotic cell death (Hara et al 2005;Nakamura et al 2015). The S-nitrosylation inhibits its catalytic activity as a glycolytic enzyme, and enables GAPDH to physically associate with the E3 ubiquitin ligase Siah1 (Padgett & Whorton 1995;Hara et al 2005;Sen et al 2008).…”

Section: Introductionmentioning

confidence: 99%

S-nitrosylated GAPDH mediates neuronal apoptosis induced by amyotrophic lateral sclerosis-associated mutant SOD1^G93A

Lee

Lim

Roh

et al. 2016

Animal Cells and Systems

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with the selective loss of motor neurons in the brain, brain stem, and spinal cord. A number of the mutants of the human gene for superoxide dismutase 1 (SOD1) have been shown to cause familial ALS as a result of gain-offunction toxicity by an unknown mechanism. In this study, we show that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) functions as a critical mediator of the apoptotic cell death signaling cascade induced by the ALS-associated G93A mutant of human SOD1 [SOD1(G93A)]. We observed that SOD1(G93A) induces S-nitrosylation of GAPDH and the subsequent binding of GAPDH and Siah1 in NSC34 motor neuron-like cells. Furthermore, SOD1(G93A) promoted nuclear translocation of S-nitrosylated GAPDH in the cells. In addition, SOD1(G93A)-induced apoptotic cell death was inhibited by deprenyl, a chemical inhibitor of GAPDH S-nitrosylation, in NSC34 cells. Taken together, our findings suggest that S-nitrosylation of GAPDH plays a critical role in SOD1(G93A)-induced neuronal apoptosis. ARTICLE HISTORY

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Aberrant protein S-nitrosylation contributes to the pathophysiology of neurodegenerative diseases

Cited by 140 publications

References 115 publications

S -nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration

S -nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration

MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress

S-nitrosylated GAPDH mediates neuronal apoptosis induced by amyotrophic lateral sclerosis-associated mutant SOD1^G93A

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Aberrant protein S-nitrosylation contributes to the pathophysiology of neurodegenerative diseases

Cited by 140 publications

References 115 publications

S -nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration

S -nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration

MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress

S-nitrosylated GAPDH mediates neuronal apoptosis induced by amyotrophic lateral sclerosis-associated mutant SOD1G93A

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S-nitrosylated GAPDH mediates neuronal apoptosis induced by amyotrophic lateral sclerosis-associated mutant SOD1^G93A