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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Epileptic Syndromes
  • Female
  • Fibroblasts / metabolism
  • Gene Expression
  • Humans
  • Lipids / blood*
  • Male
  • NF-E2-Related Factor 2 / metabolism*
  • Nitric Oxide Synthase Type II / metabolism
  • Oxidative Stress
  • Protein-Serine-Threonine Kinases / genetics*
  • Rett Syndrome / blood
  • Rett Syndrome / genetics*
  • Scavenger Receptors, Class B / genetics*
  • Scavenger Receptors, Class B / metabolism
  • Spasms, Infantile / blood
  • Spasms, Infantile / genetics*
  • Up-Regulation

Substances

  • Lipids
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • SCARB1 protein, human
  • Scavenger Receptors, Class B
  • NOS2 protein, human
  • Nitric Oxide Synthase Type II
  • Protein-Serine-Threonine Kinases
  • CDKL5 protein, human

Supplementary concepts

  • CDKL5 deficiency disorder