4-hydroxynonenal protein adducts: Key mediator in Rett syndrome oxinflammation

Free Radic Biol Med. 2017 Oct:111:270-280. doi: 10.1016/j.freeradbiomed.2016.12.045. Epub 2017 Jan 5.

Abstract

In the last 15 years a strong correlation between oxidative stress (OxS) and Rett syndrome (RTT), a rare neurodevelopmental disorder known to be caused in 95% of the cases, by a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, has been well documented. Here, we revised, summarized and discussed the current knowledge on the role of lipid peroxidation byproducts, with special emphasis on 4-hydroxynonenal (4HNE), in RTT pathophysiology. The posttranslational modifications of proteins via 4HNE, known as 4HNE protein adducts (4NHE-PAs), causing detrimental effects on protein functions, appear to contribute to the clinical severity of the syndrome, since their levels increase significantly during the subsequent 4 clinical stages, reaching the maximum degree at stage 4, represented by a late motor deterioration. In addition, 4HNE-PA are only partially removed due to the compromised functionality of the proteasome activity, contributing therefore to the cellular damage in RTT. All this will lead to a characteristic subclinical inflammation, defined "OxInflammation", derived by a positive feedback loop between OxS byproducts and inflammatory mediators that in a long run further aggravates the clinical features of RTT patients. Therefore, in a pathology completely orphan of any therapy, aiming 4HNE as a therapeutic target could represent a coadjuvant treatment with some beneficial impact in these patients.‬‬‬.

Keywords: CDKL5; FOXG1; Inflammation; Isoprostanes; MecP2; Orphan disease; Oxidative stress; Rare disease.

Publication types

  • Review

MeSH terms

  • Aldehydes / metabolism*
  • Brain / metabolism*
  • Brain / pathology
  • Feedback, Physiological
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Inflammation
  • Isoprostanes / metabolism
  • Lipid Peroxidation / genetics*
  • Methyl-CpG-Binding Protein 2 / genetics*
  • Methyl-CpG-Binding Protein 2 / metabolism
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Oxidative Stress
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Processing, Post-Translational*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Rett Syndrome / genetics
  • Rett Syndrome / metabolism*
  • Rett Syndrome / pathology

Substances

  • Aldehydes
  • FOXG1 protein, human
  • Forkhead Transcription Factors
  • Isoprostanes
  • MECP2 protein, human
  • Methyl-CpG-Binding Protein 2
  • Nerve Tissue Proteins
  • Protein Serine-Threonine Kinases
  • CDKL5 protein, human
  • Proteasome Endopeptidase Complex
  • 4-hydroxy-2-nonenal