title: Scavenger Receptor B1 oxidative post-translational modifications are responsible for its loss in Rett syndrome.
abstract: The modulation of the HDL receptor scavenger receptor B1 (SRB1) was evaluated in skin fibroblasts isolated from Rett syndrome (RTT) patients, a rare neurodevelopmental disorder affecting almost exclusively females associated in up to 95% of cases to de novo loss-of-function mutations in the X-chromosome-linked gene encoding the methyl-CpG-binding protein 2 (MeCP2). Patients showed an altered plasma lipid profile, while their skin fibroblasts showed a dramatic reduction in SRB1 (immunogold, Western blot and immunohistochemistry). The decreased SRB1 levels were demonstrated to be the consequence of its binding with 4-hydroxy-2-nonenal (4HNE), a product of lipid peroxidation, and its increased ubiquitination. Therefore the loss of SRB1 in RTT cells is a consequence of the chronic oxidative stress status present in RTT. In addition RTT fibroblast presented high intracellular levels of H2O2 and 4HNE protein adducts. This finding was correlated with the constitutive activation of NADPH oxidase (NOX) and was reverted by DPI (NOX inhibitor) or Desferal (Iron chelator) pre-treatment. To confirm the alteration of status redox in RTT cells, the activity of several enzymes involved in protecting the cell from OS was also evaluated. Glutathione peroxidase (GPx), Supeoxide dismutase and Glucose-6-phosphate dehydrogenase (G6PDH) activity were decreased respect to control. These data paralleled with a constitutive activation of NRF2 and elevated gene expression of Heme oxigenase-1 (HO-1) and NAD(P)H dehydrogenase quinone 1 (NQO-1). Of note, when NRF2 pathway was stimulated via exogenous oxidants, RTT fibroblast did not respond as the control cells.
authors.affiliation: University of Ferrara, Life Sciences and Biotechnology, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Valacchi
authors.affiliation: University of Ferrara, Life Sciences and Biotechnology, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sticozzi
authors.affiliation: University of Ferrara, Life Sciences and Biotechnology, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Belmonte
authors.affiliation: University of Ferrara, Life Sciences and Biotechnology, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Cervellati
authors.affiliation: University of Siena, Molecular and Developmental Medicine, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pecorelli
authors.affiliation: University of Siena, Molecular and Developmental Medicine, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Signorini
authors.affiliation: University of Siena, Molecular and Developmental Medicine, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Leoncini
authors.affiliation: University of Siena, Molecular and Developmental Medicine, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Ciccoli
authors.affiliation: Azienda Ospedaliera Senese (Intensive Care), S. M. Le Scotte General Hospital, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: De Felice
authors.affiliation: CNR (IRCCS Neuromed, Pozzilli, Italy), Institute of Bioscience and BioResources UOS, Italy.
authors.forename: Floriana
authors.initials: F
authors.lastname: Della Ragione
authors.affiliation: CNR (IRCCS Neuromed, Pozzilli, Italy), Institute of Bioscience and BioResources UOS, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Scalabri
authors.affiliation: CNR (IRCCS Neuromed, Pozzilli, Italy), Institute of Bioscience and BioResources UOS, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Marracino
authors.affiliation: CNR (IRCCS Neuromed, Pozzilli, Italy), Institute of Bioscience and BioResources UOS, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Madonna
authors.affiliation: CNR (IRCCS Neuromed, Pozzilli, Italy), Institute of Bioscience and BioResources UOS, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Esposito
authors.affiliation: Azienda Ospedaliera Senese (Neuropsichiatria infantile), Italy.
authors.forename: Hayek
authors.initials: H
authors.lastname: Joussef
authors.affiliation: University of Ferrara, Scienze biomediche e chirurgico specialistiche, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Cervellati
authors.affiliation: CNR (IRCCS Neuromed, Pozzilli, Italy), Institute of Bioscience and BioResources UOS, Italy.
authors.forename: Filosa
authors.initials: F
authors.lastname: Stefania