Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models

Nat Genet. 2014 Feb;46(2):152-60. doi: 10.1038/ng.2853. Epub 2013 Dec 15.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal, late-onset neurodegenerative disease primarily affecting motor neurons. A unifying feature of many proteins associated with ALS, including TDP-43 and ataxin-2, is that they localize to stress granules. Unexpectedly, we found that genes that modulate stress granules are strong modifiers of TDP-43 toxicity in Saccharomyces cerevisiae and Drosophila melanogaster. eIF2α phosphorylation is upregulated by TDP-43 toxicity in flies, and TDP-43 interacts with a central stress granule component, polyA-binding protein (PABP). In human ALS spinal cord neurons, PABP accumulates abnormally, suggesting that prolonged stress granule dysfunction may contribute to pathogenesis. We investigated the efficacy of a small molecule inhibitor of eIF2α phosphorylation in ALS models. Treatment with this inhibitor mitigated TDP-43 toxicity in flies and mammalian neurons. These findings indicate that the dysfunction induced by prolonged stress granule formation might contribute directly to ALS and that compounds that mitigate this process may represent a novel therapeutic approach.

Publication types

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

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / pharmacology
  • Amyotrophic Lateral Sclerosis / genetics*
  • Analysis of Variance
  • Animals
  • Ataxins
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Drosophila melanogaster
  • Eukaryotic Initiation Factor-2 / metabolism*
  • Gene Ontology
  • High-Throughput Screening Assays
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Indoles / pharmacology*
  • Luminescent Proteins
  • Motor Neurons / metabolism
  • Nerve Tissue Proteins / metabolism
  • Phosphorylation / drug effects
  • Poly(A)-Binding Proteins / metabolism
  • RNA Interference
  • Retina / metabolism
  • Retina / ultrastructure
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins / metabolism
  • Small Molecule Libraries
  • Spinal Cord / cytology
  • Spinal Cord / metabolism

Substances

  • 7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo(2,3-d)pyrimidin-4-amine
  • Ataxins
  • DNA-Binding Proteins
  • Eukaryotic Initiation Factor-2
  • Indoles
  • Luminescent Proteins
  • Nerve Tissue Proteins
  • PUB1 protein, S cerevisiae
  • Poly(A)-Binding Proteins
  • Saccharomyces cerevisiae Proteins
  • Small Molecule Libraries
  • red fluorescent protein
  • Adenine