title: 4-hydroxynonenal protein adducts: Key mediator in Rett syndrome oxinflammation.
abstract: In the last 15 years a strong correlation between oxidative stress (OxS) and Rett syndrome (RTT), a rare neurodevelopmental disorder known to be caused in 95% of the cases, by a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, has been well documented. Here, we revised, summarized and discussed the current knowledge on the role of lipid peroxidation byproducts, with special emphasis on 4-hydroxynonenal (4HNE), in RTT pathophysiology. The posttranslational modifications of proteins via 4HNE, known as 4HNE protein adducts (4NHE-PAs), causing detrimental effects on protein functions, appear to contribute to the clinical severity of the syndrome, since their levels increase significantly during the subsequent 4 clinical stages, reaching the maximum degree at stage 4, represented by a late motor deterioration. In addition, 4HNE-PA are only partially removed due to the compromised functionality of the proteasome activity, contributing therefore to the cellular damage in RTT. All this will lead to a characteristic subclinical inflammation, defined "OxInflammation", derived by a positive feedback loop between OxS byproducts and inflammatory mediators that in a long run further aggravates the clinical features of RTT patients. Therefore, in a pathology completely orphan of any therapy, aiming 4HNE as a therapeutic target could represent a coadjuvant treatment with some beneficial impact in these patients.‬‬‬.
authors.affiliation: Plants for Human Health Institute, Department of Animal Sciences, NC State University, NC Research Campus, 600 Laureate Way, Kannapolis, NC 28081, USA; Department of Life Sciences and Biotechnology, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy. Electronic address: giuseppe.valacchi@unife.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Valacchi
authors.affiliation: Plants for Human Health Institute, Department of Animal Sciences, NC State University, NC Research Campus, 600 Laureate Way, Kannapolis, NC 28081, USA; Department of Life Sciences and Biotechnology, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pecorelli
authors.affiliation: Department of Biomedical and Specialist Surgical Sciences, Section of Medical Biochemistry, Molecular Biology and Genetics, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Cervellati
authors.affiliation: Child Neuropsychiatry Unit, University Hospital, AOUS, Viale Mario Bracci, 53100 Siena, Italy.
authors.forename: Joussef
authors.initials: J
authors.lastname: Hayek
mesh_terms: D000447:Aldehydes / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D025461:Feedback, Physiological; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D028421:Isoprostanes / Q000378:metabolism; D015227:Lipid Peroxidation / Q000235:genetics*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015518:Rett Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D000447:Aldehydes; C090173:FOXG1 protein, human; D051858:Forkhead Transcription Factors; D028421:Isoprostanes; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human; D046988:Proteasome Endopeptidase Complex; C027576:4-hydroxy-2-nonenal
keywords: CDKL5; FOXG1; Inflammation; Isoprostanes; MecP2; Orphan disease; Oxidative stress; Rare disease