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

• Published in: Neurobiology of disease Vol. 68; no. 100; pp. 66 - 77
• Main Authors: De Felice, Claudio, Della Ragione, Floriana, Signorini, Cinzia, Leoncini, Silvia, Pecorelli, Alessandra, Ciccoli, Lucia, Scalabrì, Francesco, Marracino, Federico, Madonna, Michele, Belmonte, Giuseppe, Ricceri, Laura, De Filippis, Bianca, Laviola, Giovanni, Valacchi, Giuseppe, Durand, Thierry, Galano, Jean-Marie, Oger, Camille, Guy, Alexandre, Bultel-Poncé, Valérie, Guy, Jacky, Filosa, Stefania, Hayek, Joussef, D'Esposito, Maurizio
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2014; Elsevier; Academic Press
• Subjects: Aldehydes - metabolism; Analysis of Variance; Animals; Arachidonic Acid - metabolism; Biochemistry, Molecular Biology; Brain damage; Brain Injuries - blood; Brain Injuries - etiology; Brain Injuries - pathology; Disease Models, Animal; Docosahexaenoic Acids - metabolism; Female; Gas Chromatography-Mass Spectrometry; Genomics; Isoprostanes - metabolism; Life Sciences; Lipid peroxidation; Male; Methyl-CpG-Binding Protein 2 - genetics; Mice; Mice, Inbred C57BL; Mice, Transgenic; Murine models; Mutation - genetics; Nestin - genetics; Neurobiology; Neurodevelopmental disorder; Neurology; Neurons and Cognition; Neuroprostanes - metabolism; Oxidative stress; Oxidative Stress - physiology; Rett syndrome; Rett Syndrome - blood; Rett Syndrome - complications; Rett Syndrome - genetics; Oxidative stress; Mecp2 308/x; Mecp2 308/y; Lipid peroxidation; F4-NeuroPs; Neurodevelopmental disorder; wt-Cre; MECP2; Mecp2 stop/y NestinCre; RTT; 4-HNE; 4-HNE PAs; wt; AdA; OS; BDNF; F2-IsoPs; Mecp2 stop/y; Mecp2 −/y; NPBI; F2-dihomo-IsoPs; ARA; IsoPs; PSV; Murine models; CRE; ROS; Rett syndrome; Brain damage; DHA; PUFAs; ASDs; AUs; adrenic acid; methyl-CpG-binding protein 2 — mouse gene; 4-hydroxy-2-nonenal protein adducts; Lox/stop pre-symptomatic hemizygous mice; methyl-CpG-binding protein 2 — human protein; autism spectrum disorders; brain-derived neurotrophic factor; arachidonic acid; symptomatic Mecp2 308-mutated hemizygous males; F 2-dihomo-isoprostanes; F 2-isoprostanes; 4-HNE protein adducts; wild type; methyl-CpG-binding protein 2 — mouse protein; Preserved Speech Variant; arbitrary units; polyunsaturated fatty acids; F 4-neuroprostanes; F 2-IsoPs; isoprostanes; docosahexaenoic acid; reactive oxygen species; 4-hydroxy-2-nonenal; non-protein-bound iron; hemizygous null mice; wild type expressing Cre recombinase; F 2-dihomo-IsoPs; symptomatic Mecp2 308-mutated females; methyl-CpG-binding protein 2 — human gene; Cre-Recombinase; rescued Lox/stop mice ( Mecp2 reactivated in the nervous tissue); F 4-NeuroPs; oxidative stress
• ISSN: 0969-9961; 1095-953X; 1095-953X
• DOI: 10.1016/j.nbd.2014.04.006

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. •Oxidative damage is demonstrated in the brain, and more specifically in the neurons, of Mecp2 mutant mouse models.•A direct evidence between enhanced oxidative stress and Mecp2 deficiency is provided.•Oxidative damage precedes the behavioral abnormalities in Mecp2 mutant mice.•Mecp2 is likely involved in the protection of the brain from oxidative stress.