4-Hydroxynonenal induces persistent insolubilization of TDP-43 and alters its intracellular localization

Biochem Biophys Res Commun. 2015 Jul;463(1-2):82-7. doi: 10.1016/j.bbrc.2015.05.027. Epub 2015 May 18.

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive degeneration of motor neurons. TDP-43 has been found to be a major component of ubiquitin-positive inclusions in ALS. Aberrant TDP-43, which is found in inclusions, is phosphorylated and is re-distributed from the nucleus to the cytoplasm. Alterations of TDP-43 protein, particularly insolubilization/aggregation and cytosolic distribution are thought to be involved in the pathogenesis of ALS. Levels of 4-hydroxynonenal (HNE), a marker of oxidative stress, have been reported to be elevated in sporadic ALS patients. However, the effects of HNE on TDP-43 are unclear. In this study, we found that HNE treatment of cells causes insolubilization, phosphorylation, and partial cytosolic localization of TDP-43. HNE-induced cytosolic TDP-43 was diffusely localized and only a small proportion of TDP-43 localized to stress granules, which are transient structures. HNE-induced TDP-43 insolubilization and phosphorylation were even observed 24 h after washout of HNE. We also showed that the cysteine residues of TDP-43 are responsible for HNE-induced insolubilization of TDP-43. Our results indicate that HNE can cause biochemical changes of TDP-43, which resemble the aberrant alterations of this protein in ALS, and suggest that upregulation of HNE could be a risk factor for ALS.

Keywords: ALS; HNE; Oxidative stress; TDP-43.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / metabolism*
  • Aldehydes / pharmacology
  • Amyotrophic Lateral Sclerosis / etiology
  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • Biomarkers / metabolism
  • COS Cells
  • Cell Nucleus / metabolism
  • Chlorocebus aethiops
  • Cytosol / metabolism
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Oxidative Stress
  • Phosphorylation
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Risk Factors
  • Solubility

Substances

  • Aldehydes
  • Biomarkers
  • DNA-Binding Proteins
  • Recombinant Proteins
  • TARDBP protein, human
  • 4-hydroxy-2-nonenal