Giuseppe Valacchi, Alessandra Pecorelli, Carlo Cervellati, Joussef Hayek. 4-hydroxynonenal protein adducts: Key mediator in Rett syndrome oxinflammation. Free Radical Biology and Medicine (2017).
a. Plants for Human Health Institute, Department of Animal Sciences, NC State University, NC Research Campus, 600 Laureate Way, Kannapolis, NC 28081, USA
b. Department of Life Sciences and Biotechnology, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy
c. 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
d. Child Neuropsychiatry Unit, University Hospital, AOUS, Viale Mario Bracci, 53100 Siena, Italy
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.