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Free Radic Biol Med. 2015 Sep;86:156-65. doi: 10.1016/j.freeradbiomed.2015.05.010. Epub 2015 May 22.

Alteration of serum lipid profile, SRB1 loss, and impaired Nrf2 activation in CDKL5 disorder.

Author information

1
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.
2
Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
3
Medical Genetics, University of Siena, Siena, Italy.
4
Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
5
Neonatal Intensive Care Unit, Azienda Ospedaliera Universitaria Senese, "Santa Maria alle Scotte" General Hospital, Siena, Italy.
6
Child Neuropsychiatry Unit, Azienda Ospedaliera Universitaria Senese, "Santa Maria alle Scotte" General Hospital, Siena, Italy.
7
Medical Genetics, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
8
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.
9
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.

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.

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

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