Quantitative proteomics of synaptosome <i>S</i>‐nitrosylation in Alzheimer’s disease

Wijasa, Teodora Stella; Sylvester, Marc; Brocke‐Ahmadinejad, Nahal; Schwartz, Stephanie; Santarelli, Francesco; Gieselmann, Volkmar; Klockgether, Thomas; Brosseron, Frederic; Heneka, Michael T.

doi:10.1111/jnc.14870

Cited by 33 publications

(30 citation statements)

References 106 publications

(128 reference statements)

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“…Excessive NO production reported in prion disease, AD, and PD is inducing aberrant posttranslational protein modifications and uncontrolled neurotoxic nitrergic signaling (6)(7)(8)(9). Protein cysteine residues can be directly and reversibly S-nitrosylated by NO (9) which can lead to protein dysfunction to facilitate disease progression (10,11). NO also reacts with free radicals such as superoxide anion O 2…”

mentioning

confidence: 99%

Inhibition of neuroinflammatory nitric oxide signaling suppresses glycation and prevents neuronal dysfunction in mouse prion disease

Bourgognon

Spiers

Robinson

et al. 2021

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

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Several neurodegenerative diseases associated with protein misfolding (Alzheimer’s and Parkinson’s disease) exhibit oxidative and nitrergic stress following initiation of neuroinflammatory pathways. Associated nitric oxide (NO)-mediated posttranslational modifications impact upon protein functions that can exacerbate pathology. Nonenzymatic and irreversible glycation signaling has been implicated as an underlying pathway that promotes protein misfolding, but the direct interactions between both pathways are poorly understood. Here we investigated the therapeutic potential of pharmacologically suppressing neuroinflammatory NO signaling during early disease progression of prion-infected mice. Mice were injected daily with an NO synthase (NOS) inhibitor at early disease stages, hippocampal gene and protein expression levels of oxidative and nitrergic stress markers were analyzed, and electrophysiological characterization of pyramidal CA1 neurons was performed. Increased neuroinflammatory signaling was observed in mice between 6 and 10 wk postinoculation (w.p.i.) with scrapie prion protein. Their hippocampi were characterized by enhanced nitrergic stress associated with a decline in neuronal function by 9 w.p.i. Daily in vivo administration of the NOS inhibitor L-NAME between 6 and 9 w.p.i. at 20 mg/kg prevented the functional degeneration of hippocampal neurons in prion-diseased mice. We further found that this intervention in diseased mice reduced 3-nitrotyrosination of triose-phosphate isomerase, an enzyme involved in the formation of disease-associated glycation. Furthermore, L-NAME application led to a reduced expression of the receptor for advanced glycation end-products and the diminished accumulation of hippocampal prion misfolding. Our data suggest that suppressing neuroinflammatory NO signaling slows functional neurodegeneration and reduces nitrergic and glycation-associated cellular stress.

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mentioning

confidence: 99%

Inhibition of neuroinflammatory nitric oxide signaling suppresses glycation and prevents neuronal dysfunction in mouse prion disease

Bourgognon

Spiers

Robinson

et al. 2021

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

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“…The induction of nitric oxide synthase type 2 leads to increased nitric oxide levels and S -NO of cysteine residues ( Paula et al, 2010 ). An isobaric tag approach, iodoTMT, was used to reveal the S -NO sites on Cys residues of NOS2-dependent S -NO of synaptic proteins in mild cognitive impairment (MCI) and AD and human control brain tissues ( Wijasa et al, 2020 ). Of 291 and 295 S -NO proteins identified in synaptosome fractions, 16 and 9 S -NO proteins were significantly increased in AD vs. MCI brains and AD vs. Ctrl, respectively ( Wijasa et al, 2020 ).…”

Section: Cysteine Oxidation In Neurodegenerative Diseasesmentioning

confidence: 99%

Proteomic Approaches to Study Cysteine Oxidation: Applications in Neurodegenerative Diseases

Pham

Buczek

Mead

et al. 2021

Front. Mol. Neurosci.

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Oxidative stress appears to be a key feature of many neurodegenerative diseases either as a cause or consequence of disease. A range of molecules are subject to oxidation, but in particular, proteins are an important target and measure of oxidative stress. Proteins are subject to a range of oxidative modifications at reactive cysteine residues, and depending on the level of oxidative stress, these modifications may be reversible or irreversible. A range of experimental approaches has been developed to characterize cysteine oxidation of proteins. In particular, mass spectrometry-based proteomic methods have emerged as a powerful means to identify and quantify cysteine oxidation sites on a proteome scale; however, their application to study neurodegenerative diseases is limited to date. Here we provide a guide to these approaches and highlight the under-exploited utility of these methods to measure oxidative stress in neurodegenerative diseases for biomarker discovery, target engagement and to understand disease mechanisms.

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“…Most often, such modifications inhibit protein functions. Selected studies of the S-nitrosylation proteome in AD identified key proteins with altered functions associated with antioxidant, glycolysis, mitochondrial export, calcium homeostasis, synapses, apoptosis, mitochondrial dynamics, protein folding, and neuroinflammation, among other functions [ 113 , 114 , 115 , 116 ]. Many of these proteins are the same as those modified by other indices of oxidative and nitrosative stress noted above.…”

Section: Oxidative and Nitrosative Modifications Of Mitochondrial mentioning

confidence: 99%

Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease

Butterfield

Boyd‐Kimball

2020

Antioxidants

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Oxidative and nitrosative stress are widely recognized as critical factors in the pathogenesis and progression of Alzheimer disease (AD) and its earlier stage, amnestic mild cognitive impairment (MCI). A major source of free radicals that lead to oxidative and nitrosative damage is mitochondria. This review paper discusses oxidative and nitrosative stress and markers thereof in the brain, along with redox proteomics, which are techniques that have been pioneered in the Butterfield laboratory. Selected biological alterations in—and oxidative and nitrosative modifications of—mitochondria in AD and MCI and systems of relevance thereof also are presented. The review article concludes with a section on the implications of mitochondrial oxidative and nitrosative stress in MCI and AD with respect to imaging studies in and targeted therapies toward these disorders. Taken together, this review provides support for the notion that brain mitochondrial alterations in AD and MCI are key components of oxidative and nitrosative stress observed in these two disorders, and as such, they provide potentially promising therapeutic targets to slow—and hopefully one day stop—the progression of AD, which is a devastating dementing disorder.

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Quantitative proteomics of synaptosome S‐nitrosylation in Alzheimer’s disease

Cited by 33 publications

References 106 publications

Inhibition of neuroinflammatory nitric oxide signaling suppresses glycation and prevents neuronal dysfunction in mouse prion disease

Inhibition of neuroinflammatory nitric oxide signaling suppresses glycation and prevents neuronal dysfunction in mouse prion disease

Proteomic Approaches to Study Cysteine Oxidation: Applications in Neurodegenerative Diseases

Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease

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