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Nitrosative stress, hypernitrosylation, and autoimmune responses to nitrosylated proteins: new pathways in neuroprogressive disorders Including depression and chronic fatigue syndrome.
journal contribution
posted on 2017-08-01, 00:00 authored by G Morris, Michael BerkMichael Berk, H Klein, Ken WalderKen Walder, P Galecki, M. MaesNitric oxide plays an indispensable role in modulating cellular signaling and redox pathways. This role is mainly effected by the readily reversible nitrosylation of selective protein cysteine thiols. The reversibility and sophistication of this signaling system is enabled and regulated by a number of enzymes which form part of the thioredoxin, glutathione, and pyridoxine antioxidant systems. Increases in nitric oxide levels initially lead to a defensive increase in the number of nitrosylated proteins in an effort to preserve their function. However, in an environment of chronic oxidative and nitrosative stress (O&NS), nitrosylation of crucial cysteine groups within key enzymes of the thioredoxin, glutathione, and pyridoxine systems leads to their inactivation thereby disabling denitrosylation and transnitrosylation and subsequently a state described as "hypernitrosylation." This state leads to the development of pathology in multiple domains such as the inhibition of enzymes of the electron transport chain, decreased mitochondrial function, and altered conformation of proteins and amino acids leading to loss of immune tolerance and development of autoimmunity. Hypernitrosylation also leads to altered function or inactivation of proteins involved in the regulation of apoptosis, autophagy, proteomic degradation, transcription factor activity, immune-inflammatory pathways, energy production, and neural function and survival. Hypernitrosylation, as a consequence of chronically elevated O&NS and activated immune-inflammatory pathways, can explain many characteristic abnormalities observed in neuroprogressive disease including major depression and chronic fatigue syndrome/myalgic encephalomyelitis. In those disorders, increased bacterial translocation may drive hypernitrosylation and autoimmune responses against nitrosylated proteins.
History
Journal
Molecular neurobiologyVolume
54Issue
6Pagination
4271 - 4291Publisher
SpringerLocation
Berlin, GermanyPublisher DOI
eISSN
1559-1182Language
engPublication classification
C Journal article; C1 Refereed article in a scholarly journalCopyright notice
2016, SpringerUsage metrics
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Categories
Keywords
CytokinesDepressionImmuneLeaky gutMyalgic encephalomyelitisNitric oxideNitrosative stressScience & TechnologyLife Sciences & BiomedicineNeurosciencesNeurosciences & NeurologyLeakygutMyalgicencephalomyelitisNF-KAPPA-BGLYCOGEN-SYNTHASE KINASE-3MITOCHONDRIAL COMPLEX-INITRIC-OXIDE PRODUCTIONS-NITROSYLATIONOXIDATIVE STRESSSIGNAL-TRANSDUCTIONDISULFIDE-ISOMERASETYROSINE NITRATIONCYSTEINE RESIDUES