Oxidative brain damage in Mecp2-mutant murine models of Rett syndrome.
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.
Neonatal Intensive Care Unit, University Hospital AOUS, Siena, Italy. Electronic address: geniente@gmail.com.
Claudio
C
De Felice
Institute of Genetics and Biophysics "A. Buzzati-Traverso", Naples, Italy; IRCCS Neuromed, Pozzilli, Italy.
Floriana
F
Della Ragione
Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
Cinzia
C
Signorini
Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy; Child Neuropsychiatry Unit, University Hospital AOUS, Siena, Italy.
Silvia
S
Leoncini
Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy; Child Neuropsychiatry Unit, University Hospital AOUS, Siena, Italy.
Alessandra
A
Pecorelli
Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
Lucia
L
Ciccoli
IRCCS Neuromed, Pozzilli, Italy.
Francesco
F
Scalabrì
IRCCS Neuromed, Pozzilli, Italy.
Federico
F
Marracino
IRCCS Neuromed, Pozzilli, Italy.
Michele
M
Madonna
Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
Giuseppe
G
Belmonte
Department of Cell Biology and Neuroscience, ISS, Rome, Italy.
Laura
L
Ricceri
Department of Cell Biology and Neuroscience, ISS, Rome, Italy.
Bianca
B
De Filippis
Department of Cell Biology and Neuroscience, ISS, Rome, Italy.
Giovanni
G
Laviola
Department of Life Sciences and Biotechnologies, University of Ferrara, Ferrara, Italy.
Giuseppe
G
Valacchi
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247-CNRS-UM I-UM II-ENSCM, Montpellier, France.
Thierry
T
Durand
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247-CNRS-UM I-UM II-ENSCM, Montpellier, France.
Jean-Marie
JM
Galano
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247-CNRS-UM I-UM II-ENSCM, Montpellier, France.
Camille
C
Oger
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247-CNRS-UM I-UM II-ENSCM, Montpellier, France.
Alexandre
A
Guy
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247-CNRS-UM I-UM II-ENSCM, Montpellier, France.
Valérie
V
Bultel-Poncé
Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, United Kingdom.
Jacky
J
Guy
Institute of Genetics and Biophysics "A. Buzzati-Traverso", Naples, Italy; IRCCS Neuromed, Pozzilli, Italy.
Stefania
S
Filosa
Child Neuropsychiatry Unit, University Hospital AOUS, Siena, Italy.
Joussef
J
Hayek
Institute of Genetics and Biophysics "A. Buzzati-Traverso", Naples, Italy; IRCCS Neuromed, Pozzilli, Italy. Electronic address: maurizio.desposito@igb.cnr.it.
Maurizio
M
D'Esposito
D000447:Aldehydes / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001930:Brain Injuries / Q000097:blood / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000378:metabolism; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D028421:Isoprostanes / Q000378:metabolism; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D064231:Nestin / Q000235:genetics; D058632:Neuroprostanes / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D015518:Rett Syndrome / Q000097:blood / Q000150:complications* / Q000235:genetics*
D000447:Aldehydes; D028421:Isoprostanes; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; C577485:Nes protein, mouse; D064231:Nestin; D058632:Neuroprostanes; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; C027576:4-hydroxy-2-nonenal
Brain damage; Lipid peroxidation; Murine models; Neurodevelopmental disorder; Oxidative stress; Rett syndrome