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.‬‬‬

4-hydroxynonenal protein adducts: Key mediator in Rett syndrome oxinflammation

VALACCHI, Giuseppe
;
PECORELLI, Alessandra;CERVELLATI, Carlo;
2017

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.‬‬‬
Valacchi, Giuseppe; Pecorelli, Alessandra; Cervellati, Carlo; Hayek, Joussef
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11392/2362105
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