Functional Contribution of the Transcription Factor ATF4 to the Pathogenesis of Amyotrophic Lateral Sclerosis

PLoS One. 2013 Jul 18;8(7):e66672. doi: 10.1371/journal.pone.0066672. Print 2013.

Abstract

Endoplasmic reticulum (ER) stress represents an early pathological event in amyotrophic lateral sclerosis (ALS). ATF4 is a key ER stress transcription factor that plays a role in both adaptation to stress and the activation of apoptosis. Here we investigated the contribution of ATF4 to ALS. ATF4 deficiency reduced the rate of birth of SOD1(G86R) transgenic mice. The fraction of ATF4(-/-)-SOD1(G85R) transgenic mice that were born are more resistant to develop ALS, leading to delayed disease onset and prolonged life span. ATF4 deficiency completely attenuated the induction of pro-apoptotic genes, including BIM and CHOP, and also led to quantitative changes in the ER protein homeostasis network. Unexpectedly, ATF4 deficiency enhanced mutant SOD1 aggregation at the end stage of the disease. Studies in the motoneuron cell line NSC34 demonstrated that knocking down ATF4 enhances mutant SOD1 aggregation possibly due to alteration in the redox status of the cell. Our results support a functional role of ATF4 in ALS, offering a novel target for disease intervention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / deficiency
  • Activating Transcription Factor 4 / metabolism*
  • Amyotrophic Lateral Sclerosis / physiopathology*
  • Animals
  • Blotting, Western
  • Cell Line
  • DNA Primers / genetics
  • Endoplasmic Reticulum Stress / physiology*
  • Gene Expression Regulation / genetics*
  • Mice
  • Mice, Transgenic
  • Microscopy, Fluorescence
  • Mutation, Missense / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase-1

Substances

  • Atf4 protein, mouse
  • DNA Primers
  • Activating Transcription Factor 4
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1

Grant support

This work was funded by The Muscular Dystrophy Association and ALS Therapy Alliance; Millennium Institute no. P09-015-F, ACT1109 and FONDEF D11I1007; FONDECYT no. 1100176; AD Association (CH), FONDECYT 11121524 (SM), ALSA 1829 The Milton-Safenowitz Post-Doctoral Fellowship (SM), Insercion Capital Humano en la Academia 79100007. VV and MC received a CONICYT PhD fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.