title: Exploring the possible link between MeCP2 and oxidative stress in Rett syndrome.
abstract: Rett syndrome (RTT, MIM 312750) is a rare and orphan progressive neurodevelopmental disorder affecting girls almost exclusively, with a frequency of 1/15,000 live births of girls. The disease is characterized by a period of 6 to 18 months of apparently normal neurodevelopment, followed by early neurological regression, with a progressive loss of acquired cognitive, social, and motor skills. RTT is known to be caused in 95% of the cases by sporadic de novo loss-of-function mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene encoding methyl-CpG binding protein 2 (MeCP2), a nuclear protein able to regulate gene expression. Despite almost two decades of research into the functions and role of MeCP2, little is known about the mechanisms leading from MECP2 mutation to the disease. Oxidative stress (OS) is involved in the pathogenic mechanisms of several neurodevelopmental and neurodegenerative disorders, although in many cases it is not clear whether OS is a cause or a consequence of the pathology. Fairly recently, the presence of a systemic OS has been demonstrated in RTT patients with a strong correlation with the patients' clinical status. The link between MECP2 mutation and the redox imbalance found in RTT is not clear. Animal studies have suggested a possible direct correlation between Mecp2 mutation and increased OS levels. In addition, the restoration of Mecp2 function in astrocytes significantly improves the developmental outcome of Mecp2-null mice and reexpression of Mecp2 gene in the brain of null mice restored oxidative damage, suggesting that Mecp2 loss of function can be involved in oxidative brain damage. Starting from the evidence that oxidative damage in the brain of Mecp2-null mice precedes the onset of symptoms, we evaluated whether, based on the current literature, the dysfunctions described in RTT could be a consequence or, in contrast, could be caused by OS. We also analyzed whether therapies that at least partially treated some RTT symptoms can play a role in defense against OS. At this stage we can propose that OS could be one of the main causes of the dysfunctions observed in RTT. In addition, the major part of the therapies recommended to alleviate RTT symptoms have been shown to interfere with oxidative homeostasis, suggesting that MeCP2 could somehow be involved in the protection of the brain from OS.
authors.affiliation: Institute of Biosciences and BioResources-CNR, UOS Naples, Italy; IRCCS Neuromed, Pozzilli, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Filosa
authors.affiliation: Child Neuropsychiatry Unit, University General Hospital, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pecorelli
authors.affiliation: Institute of Genetics and Biophysics "A. Buzzati-Traverso"-CNR, Naples, Italy; IRCCS Neuromed, Pozzilli, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Esposito
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Department of Food and Nutrition, Kyung Hee University, Seoul, South Korea. Electronic address: giuseppe.valacchi@unife.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Valacchi
authors.affiliation: Child Neuropsychiatry Unit, University General Hospital, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Joussef
authors.initials: J
authors.lastname: Hajek
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D018384:Oxidative Stress; D015518:Rett Syndrome / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D051783:Methyl-CpG-Binding Protein 2
keywords: 4-Hydroxy-2-nonenal; Brain damage; Brain-derived neurotrophic factor; Methyl-CpG-binding protein 2; Mitochondria; Neurodevelopmental disorder; Oxidative stress; Rett syndrome