Oxidative brain damage in Mecp2-mutant murine models of Rett syndrome

Claudio De Felice, Floriana Della Ragione, Cinzia Signorini, Silvia Leoncini, Alessandra Pecorelli, Lucia Ciccoli, Francesco Scalabrì, Federico Marracino, Michele Madonna, Giuseppe Belmonte, Laura Ricceri, Bianca De Filippis, Giovanni Laviola, Giuseppe Valacchi, Thierry Durand, Jean Marie Galano, Camille Oger, Alexandre Guy, Valérie Bultel-Poncé, Jacky GuyStefania Filosa, Joussef Hayek, Maurizio D'Esposito

Research output: Contribution to journalArticle

Abstract

Rett syndrome (RTT) is a rare neurodevelopmental disorder affecting almost exclusively females, caused in the overwhelming majority of the cases by loss-of-function mutations in the gene encoding methyl-CpG binding protein 2 (MECP2). High circulating levels of oxidative stress (OS) markers in patients suggest the involvement of OS in the RTT pathogenesis. To investigate the occurrence of oxidative brain damage in Mecp2 mutant mouse models, several OS markers were evaluated in whole brains of Mecp2-null (pre-symptomatic, symptomatic, and rescued) and Mecp2-308 mutated (pre-symptomatic and symptomatic) mice, and compared to those of wild type littermates. Selected OS markers included non-protein-bound iron, isoprostanes (F2-isoprostanes, F4-neuroprostanes, F2-dihomo-isoprostanes) and 4-hydroxy-2-nonenal protein adducts. Our findings indicate that oxidative brain damage 1) occurs in both Mecp2-null (both -/y and stop/y) and Mecp2-308 (both 308/y males and 308/+ females) mouse models of RTT; 2) precedes the onset of symptoms in both Mecp2-null and Mecp2-308 models; and 3) is rescued by Mecp2 brain specific gene reactivation. Our data provide direct evidence of the link between Mecp2 deficiency, oxidative stress and RTT pathology, as demonstrated by the rescue of the brain oxidative homeostasis following brain-specifically Mecp2-reactivated mice. The present study indicates that oxidative brain damage is a previously unrecognized hallmark feature of murine RTT, and suggests that Mecp2 is involved in the protection of the brain from oxidative stress.

Original languageEnglish
Pages (from-to)66-77
Number of pages12
JournalNeurobiology of Disease
Volume68
DOIs
Publication statusPublished - 2014

Keywords

  • Brain damage
  • Lipid peroxidation
  • Murine models
  • Neurodevelopmental disorder
  • Oxidative stress
  • Rett syndrome

ASJC Scopus subject areas

  • Neurology
  • Medicine(all)

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    De Felice, C., Della Ragione, F., Signorini, C., Leoncini, S., Pecorelli, A., Ciccoli, L., Scalabrì, F., Marracino, F., Madonna, M., Belmonte, G., Ricceri, L., De Filippis, B., Laviola, G., Valacchi, G., Durand, T., Galano, J. M., Oger, C., Guy, A., Bultel-Poncé, V., ... D'Esposito, M. (2014). Oxidative brain damage in Mecp2-mutant murine models of Rett syndrome. Neurobiology of Disease, 68, 66-77. https://doi.org/10.1016/j.nbd.2014.04.006