title: Nitrosative Stress, Hypernitrosylation, and Autoimmune Responses to Nitrosylated Proteins: New Pathways in Neuroprogressive Disorders Including Depression and Chronic Fatigue Syndrome.
abstract: Nitric 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.
authors.affiliation: Tir Na Nog, Bryn Road seaside 87, Llanelli, SA152LW, Wales, UK.
authors.forename: Gerwyn
authors.initials: G
authors.lastname: Morris
authors.affiliation: IMPACT Strategic Research Centre, School of Medicine, Deakin University, P.O. Box 291, Geelong, 3220, Australia.|Orygen Youth Health Research Centre and the Centre of Youth Mental Health, Poplar Road 35, Parkville, 3052, Australia.|The Florey Institute for Neuroscience and Mental Health, University of Melbourne, Kenneth Myer Building, Royal Parade 30, Parkville, 3052, Australia.|Department of Psychiatry, Royal Melbourne Hospital, University of Melbourne, Level 1 North, Main Block, Parkville, 3052, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
authors.affiliation: Department of Psychiatry, University of Groningen, UMCG, Groningen, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Klein
authors.affiliation: Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, Australia.
authors.forename: Ken
authors.initials: K
authors.lastname: Walder
authors.affiliation: Department of Adult Psychiatry, Medical University of Lodz, Łódź, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Galecki
authors.affiliation: Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. dr.michaelmaes@hotmail.com.|Department of Psychiatry, Faculty of Medicine, State University of Londrina, Londrina, Brazil. dr.michaelmaes@hotmail.com.|Department of Psychiatry, Medical University Plovdiv, Plovdiv, Bulgaria. dr.michaelmaes@hotmail.com.|Revitalis, Waalre, The Netherlands. dr.michaelmaes@hotmail.com.|IMPACT Strategic Research Center, Barwon Health, Deakin University, Geelong, VIC, Australia. dr.michaelmaes@hotmail.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Maes
mesh_terms: D000818:Animals; D015551:Autoimmunity; D003863:Depression / Q000276:immunology*; D015673:Fatigue Syndrome, Chronic / Q000276:immunology*; D006801:Humans; D019636:Neurodegenerative Diseases / Q000276:immunology*; D015538:Nitrosation; D000073039:Nitrosative Stress
keywords: Cytokines; Depression; Immune; Leaky gut; Myalgic encephalomyelitis; Nitric oxide; Nitrosative stress