title: Impaired enzymatic defensive activity, mitochondrial dysfunction and proteasome activation are involved in RTT cell oxidative damage.
abstract: A strong correlation between oxidative stress (OS) and Rett syndrome (RTT), a rare neurodevelopmental disorder affecting females in the 95% of the cases, has been well documented although the source of OS and the effect of a redox imbalance in this pathology has not been yet investigated. Using freshly isolated skin fibroblasts from RTT patients and healthy subjects, we have demonstrated in RTT cells high levels of H2O2 and HNE protein adducts. These findings correlated with the constitutive activation of NADPH-oxidase (NOX) and that was prevented by a NOX inhibitor and iron chelator pre-treatment, showing its direct involvement. In parallel, we demonstrated an increase in mitochondrial oxidant production, altered mitochondrial biogenesis and impaired proteasome activity in RTT samples. Further, we found that the key cellular defensive enzymes: glutathione peroxidase, superoxide dismutase and thioredoxin reductases activities were also significantly lower in RTT. Taken all together, our findings suggest that the systemic OS levels in RTT can be a consequence of both: increased endogenous oxidants as well as altered mitochondrial biogenesis with a decreased activity of defensive enzymes that leads to posttranslational oxidant protein modification and a proteasome activity impairment.
authors.affiliation: Department of Biomedical and Specialist Surgical Sciences, Section of Medical Biochemistry, Molecular Biology and Genetics, University of Ferrara, Ferrara, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Cervellati
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sticozzi
authors.affiliation: Department of Biomedical and Specialist Surgical Sciences, Section of Medical Biochemistry, Molecular Biology and Genetics, University of Ferrara, Ferrara, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Romani
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Belmonte
authors.affiliation: Institute of Biomembrane and Bioenergetics, CNR, Bari 70124, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: De Rasmo
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Bari 70124, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Signorile
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Cervellati
authors.affiliation: Department of Genetics, Erasmus University Medical Center Rotterdam, the Netherlands.
authors.forename: Chiara
authors.initials: C
authors.lastname: Milanese
authors.affiliation: Department of Genetics, Erasmus University Medical Center Rotterdam, the Netherlands.
authors.forename: Pier Giorgio
authors.initials: PG
authors.lastname: Mastroberardino
authors.affiliation: Child Neuropsychiatry Unit, University Hospital, Azienda Ospedaliera Universitaria Senese (AOUS), Siena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pecorelli
authors.affiliation: Dipartimento di Scienze Mediche, Chirurgiche e Neuroscienze, Universita' di Siena, 53100 Siena, Italy.
authors.forename: Vinno
authors.initials: V
authors.lastname: Savelli
authors.affiliation: Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA; Life and Environmental Sciences Unit, University of California at Merced, Merced, CA 95344, USA.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Forman
authors.affiliation: Child Neuropsychiatry Unit, University Hospital, Azienda Ospedaliera Universitaria Senese (AOUS), Siena, Italy.
authors.forename: Joussef
authors.initials: J
authors.lastname: Hayek
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy; Department of Food and Nutrition, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea. Electronic address: giuseppe.valacchi@unife.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Valacchi
keywords: 4HNE; Glutathione peroxidase; NADPH oxidase; Oxidative stress; Superoxide dismutase thioredoxin-reductases