title: Alteration of serum lipid profile, SRB1 loss, and impaired Nrf2 activation in CDKL5 disorder.
abstract: CDKL5 mutation is associated with an atypical Rett syndrome (RTT) variant. Recently, cholesterol homeostasis perturbation and oxidative-mediated loss of the high-density lipoprotein receptor SRB1 in typical RTT have been suggested. Here, we demonstrate an altered lipid serum profile also in CDKL5 patients with decreased levels of SRB1 and impaired activation of the defensive system Nrf2. In addition, CDKL5 fibroblasts showed an increase in 4-hydroxy-2-nonenal- and nitrotyrosine-SRB1 adducts that lead to its ubiquitination and probable degradation. This study highlights a possible common denominator between two different RTT variants (MECP2 and CDKL5) and a possible common future therapeutic target.
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy; Child Neuropsychiatry Unit, Azienda Ospedaliera Universitaria Senese, "Santa Maria alle Scotte" General Hospital, Siena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pecorelli
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Belmonte
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Meloni
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Cervellati
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Gardi
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sticozzi
authors.affiliation: Neonatal Intensive Care Unit, Azienda Ospedaliera Universitaria Senese, "Santa Maria alle Scotte" General Hospital, Siena, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: De Felice
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Signorini
authors.affiliation: Child Neuropsychiatry Unit, Azienda Ospedaliera Universitaria Senese, "Santa Maria alle Scotte" General Hospital, Siena, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Cortelazzo
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy; Child Neuropsychiatry Unit, Azienda Ospedaliera Universitaria Senese, "Santa Maria alle Scotte" General Hospital, Siena, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Leoncini
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Ciccoli
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
authors.affiliation: Life and Environmental Sciences Unit, University of California at Merced, Merced, CA 95344, USA; Andrus Gerontology Center of the Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Jay Forman
authors.affiliation: Child Neuropsychiatry Unit, Azienda Ospedaliera Universitaria Senese, "Santa Maria alle Scotte" General Hospital, Siena, Italy.
authors.forename: Joussef
authors.initials: J
authors.lastname: Hayek
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
mesh_terms: D000293:Adolescent; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D000073376:Epileptic Syndromes; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008055:Lipids / Q000097:blood*; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D015518:Rett Syndrome / Q000097:blood / Q000235:genetics*; D051122:Scavenger Receptors, Class B / Q000235:genetics* / Q000378:metabolism; D013036:Spasms, Infantile / Q000097:blood / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D008055:Lipids; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human
keywords: 4-Hydroxy-2-nonenal; Free radicals; Inducible nitric oxide synthase; Nitrotyrosine; Nuclear factor erythroid 2-related factor 2; Oxidative stress; Scavenger receptor class B; type 1