期刊
NEUROBIOLOGY OF DISEASE
卷 55, 期 -, 页码 64-75出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2013.03.015
关键词
TDP-43; ALS; Genetic models; Small molecules; ER stress; Neurodegeneration; C. elegans; Zebrafish
资金
- NIH Office of Research Infrastructure Programs [P40 0D010440]
- CIHR fellowship
- INSERM
- CHUM Foundation
- Bernice Ramsay Discovery Grant program from the ALS Society of Canada
- Muscular Dystrophy Association
- Frick Foundation for ALS Research
- Genome Quebec
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. Crown Copyright (c) 2013 Published by Elsevier Inc. All rights reserved.
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