title: Redox imbalance and morphological changes in skin fibroblasts in typical Rett syndrome.
abstract: Evidence of oxidative stress has been reported in the blood of patients with Rett syndrome (RTT), a neurodevelopmental disorder mainly caused by mutations in the gene encoding the Methyl-CpG-binding protein 2. Little is known regarding the redox status in RTT cellular systems and its relationship with the morphological phenotype. In RTT patients (n = 16) we investigated four different oxidative stress markers, F2-Isoprostanes (F2-IsoPs), F4-Neuroprostanes (F4-NeuroPs), nonprotein bound iron (NPBI), and (4-HNE PAs), and glutathione in one of the most accessible cells, that is, skin fibroblasts, and searched for possible changes in cellular/intracellular structure and qualitative modifications of synthesized collagen. Significantly increased F4-NeuroPs (12-folds), F2-IsoPs (7.5-folds) NPBI (2.3-folds), 4-HNE PAs (1.48-folds), and GSSG (1.44-folds) were detected, with significantly decreased GSH (-43.6%) and GSH/GSSG ratio (-3.05 folds). A marked dilation of the rough endoplasmic reticulum cisternae, associated with several cytoplasmic multilamellar bodies, was detectable in RTT fibroblasts. Colocalization of collagen I and collagen III, as well as the percentage of type I collagen as derived by semiquantitative immunofluorescence staining analyses, appears to be significantly reduced in RTT cells. Our findings indicate the presence of a redox imbalance and previously unrecognized morphological skin fibroblast abnormalities in RTT patients.
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy.
authors.forename: Cinzia
authors.identifier: 0000-0003-0006-9414
authors.initials: C
authors.lastname: Signorini
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy ; Child Neuropsychiatry Unit, University Hospital Azienda Ospedaliera Universitaria Senese (AOUS), 53100 Siena, Italy.
authors.forename: Silvia
authors.identifier: 0000-0002-7027-1207
authors.initials: S
authors.lastname: Leoncini
authors.affiliation: Neonatal Intensive Care Unit, University Hospital AOUS, Policlinico "S. M. alle Scotte," 53100 Siena, Italy.
authors.forename: Claudio
authors.identifier: 0000-0002-9881-3119
authors.initials: C
authors.lastname: De Felice
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy ; Child Neuropsychiatry Unit, University Hospital Azienda Ospedaliera Universitaria Senese (AOUS), 53100 Siena, Italy.
authors.forename: Alessandra
authors.identifier: 0000-0002-5207-068X
authors.initials: A
authors.lastname: Pecorelli
authors.affiliation: Medical Genetics, University of Siena, 53100 Siena, Italy.
authors.forename: Ilaria
authors.identifier: 0000-0002-6255-9761
authors.initials: I
authors.lastname: Meloni
authors.affiliation: Medical Genetics, University of Siena, 53100 Siena, Italy.
authors.forename: Francesca
authors.identifier: 0000-0002-0988-344X
authors.initials: F
authors.lastname: Ariani
authors.affiliation: Medical Genetics, University of Siena, 53100 Siena, Italy.
authors.forename: Francesca
authors.identifier: 0000-0003-1992-1654
authors.initials: F
authors.lastname: Mari
authors.affiliation: Medical Genetics, University of Siena, 53100 Siena, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Amabile
authors.affiliation: Department of Life Sciences, University of Siena, 53100 Siena, Italy.
authors.forename: Eugenio
authors.identifier: 0000-0002-9784-2057
authors.initials: E
authors.lastname: Paccagnini
authors.affiliation: Department of Life Sciences, University of Siena, 53100 Siena, Italy.
authors.forename: Mariangela
authors.identifier: 0000-0002-4928-4652
authors.initials: M
authors.lastname: Gentile
authors.affiliation: Department of Medicine Surgery and Neuroscience, University of Siena, 53100 Siena, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Belmonte
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy ; Child Neuropsychiatry Unit, University Hospital Azienda Ospedaliera Universitaria Senese (AOUS), 53100 Siena, Italy.
authors.forename: Gloria
authors.identifier: 0000-0003-3350-4857
authors.initials: G
authors.lastname: Zollo
authors.affiliation: Department of Life Science and Biotechnologies, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Valacchi
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR 5247-CNRS-UM I-UM II-ENSCM, BP 14491 34093, Montpellier Cedex 5, France.
authors.forename: Thierry
authors.identifier: 0000-0002-0428-0746
authors.initials: T
authors.lastname: Durand
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR 5247-CNRS-UM I-UM II-ENSCM, BP 14491 34093, Montpellier Cedex 5, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Galano
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Ciccoli
authors.affiliation: Medical Genetics, University of Siena, 53100 Siena, Italy ; Genetica Medica, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
authors.affiliation: Child Neuropsychiatry Unit, University Hospital Azienda Ospedaliera Universitaria Senese (AOUS), 53100 Siena, Italy.
authors.forename: Joussef
authors.initials: J
authors.lastname: Hayek
mesh_terms: D000293:Adolescent; D000975:Antioxidants / Q000378:metabolism; D048430:Cell Shape; D003094:Collagen / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D005455:Fluorescent Antibody Technique; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D016877:Oxidants / Q000378:metabolism; D010084:Oxidation-Reduction; D015518:Rett Syndrome / Q000473:pathology*; D012867:Skin / Q000473:pathology*
chemical_list: D000975:Antioxidants; D016877:Oxidants; D003094:Collagen; D005978:Glutathione