Pharmacological reduction of ER stress protects against TDP-43 neuronal toxicity in vivo

Neurobiol Dis. 2013 Jul;55:64-75. doi: 10.1016/j.nbd.2013.03.015. Epub 2013 Apr 5.


C. elegans and D. rerio expressing mutant TAR DNA Binding Protein 43 (TDP-43) are powerful in vivo animal models for the genetics and pharmacology of amyotrophic lateral sclerosis (ALS). Using these small-animal models of ALS, we previously identified methylene blue (MB) as a potent suppressor of TDP-43 toxicity. Consequently here we investigated how MB might exert its neuroprotective properties and found that it acts through reduction of the endoplasmic reticulum (ER) stress response. We tested other compounds known to be active in the ER unfolded protein response in worms and zebrafish expressing mutant human TDP-43 (mTDP-43). We identified three compounds: salubrinal, guanabenz and a new structurally related compound phenazine, which also reduced paralysis, neurodegeneration and oxidative stress in our mTDP-43 models. Using C. elegans genetics, we showed that all four compounds act as potent suppressors of mTDP-43 toxicity through reduction of the ER stress response. Interestingly, these compounds operate through different branches of the ER unfolded protein pathway to achieve a common neuroprotective action. Our results indicate that protein-folding homeostasis in the ER is an important target for therapeutic development in ALS and other TDP-43-related neurodegenerative diseases.

Publication types

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

MeSH terms

  • Analysis of Variance
  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins / genetics
  • Cinnamates / pharmacology
  • Cinnamates / therapeutic use
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Disease Models, Animal
  • Endoplasmic Reticulum Stress / drug effects
  • Endoplasmic Reticulum Stress / genetics*
  • Escape Reaction / drug effects
  • Escape Reaction / physiology
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Guanabenz / pharmacology
  • Guanabenz / therapeutic use
  • Humans
  • Microinjections
  • Movement Disorders / drug therapy
  • Movement Disorders / etiology
  • Mutation / genetics
  • Neurons / drug effects
  • Neurons / pathology
  • Neurotoxicity Syndromes / drug therapy
  • Neurotoxicity Syndromes / genetics*
  • Neurotoxicity Syndromes / pathology
  • Neurotoxicity Syndromes / physiopathology*
  • Phenazines
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species / metabolism
  • Thiourea / analogs & derivatives
  • Thiourea / pharmacology
  • Thiourea / therapeutic use
  • Time Factors
  • Touch / physiology
  • Zebrafish
  • Zebrafish Proteins / genetics


  • Caenorhabditis elegans Proteins
  • Cinnamates
  • DNA-Binding Proteins
  • Phenazines
  • RNA, Messenger
  • Reactive Oxygen Species
  • Zebrafish Proteins
  • salubrinal
  • Green Fluorescent Proteins
  • Guanabenz
  • Thiourea