Pharmacological reduction of ER stress protects against TDP-43 neuronal toxicity in vivo
- Authors
- Vaccaro, A., Patten, S.A., Aggad, D., Julien, C., Maios, C., Kabashi, E., Drapeau, P., and Parker, J.A.
- ID
- ZDB-PUB-130418-1
- Date
- 2013
- Source
- Neurobiology of disease 55: 64-75 (Journal)
- Registered Authors
- Drapeau, Pierre
- Keywords
- TDP-43, ALS, genetic models, small molecules, ER stress, neurodegeneration, C elegans, zebrafish
- MeSH Terms
-
- Caenorhabditis elegans Proteins/genetics
- Neurotoxicity Syndromes/drug therapy
- Neurotoxicity Syndromes/genetics*
- Neurotoxicity Syndromes/pathology
- Neurotoxicity Syndromes/physiopathology*
- Cinnamates/pharmacology
- Cinnamates/therapeutic use
- Neurons/drug effects
- Neurons/pathology
- Thiourea/analogs & derivatives
- Thiourea/pharmacology
- Thiourea/therapeutic use
- Time Factors
- Endoplasmic Reticulum Stress/drug effects
- Endoplasmic Reticulum Stress/genetics*
- Analysis of Variance
- Movement Disorders/drug therapy
- Movement Disorders/etiology
- Zebrafish Proteins/genetics
- Animals, Genetically Modified
- Caenorhabditis elegans
- Guanabenz/pharmacology
- Guanabenz/therapeutic use
- Zebrafish
- Escape Reaction/drug effects
- Escape Reaction/physiology
- Reactive Oxygen Species/metabolism
- Touch/physiology
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/metabolism*
- Mutation/genetics
- Phenazines
- Green Fluorescent Proteins/genetics
- Green Fluorescent Proteins/metabolism
- Disease Models, Animal
- Microinjections
- Animals
- Humans
- RNA, Messenger/metabolism
- PubMed
- 23567652 Full text @ Neurobiol. Dis.
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.