title: Pharmacological reduction of ER stress protects against TDP-43 neuronal toxicity in vivo.
abstract: 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.
authors.affiliation: CRCHUM, Université de Montréal, Montréal, QC, Canada.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Vaccaro
authors.forename: Shunmoogum A
authors.initials: SA
authors.lastname: Patten
authors.forename: Dina
authors.initials: D
authors.lastname: Aggad
authors.forename: Carl
authors.initials: C
authors.lastname: Julien
authors.forename: Claudia
authors.initials: C
authors.lastname: Maios
authors.forename: Edor
authors.initials: E
authors.lastname: Kabashi
authors.forename: Pierre
authors.initials: P
authors.lastname: Drapeau
authors.forename: J Alex
authors.initials: JA
authors.lastname: Parker
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D002934:Cinnamates / Q000494:pharmacology / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics*; D004924:Escape Reaction / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006143:Guanabenz / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008845:Microinjections; D009069:Movement Disorders / Q000188:drug therapy / Q000209:etiology; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D010619:Phenazines; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D014110:Touch / Q000502:physiology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: D029742:Caenorhabditis elegans Proteins; D002934:Cinnamates; D004268:DNA-Binding Proteins; D010619:Phenazines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D029961:Zebrafish Proteins; C496827:salubrinal; D049452:Green Fluorescent Proteins; D006143:Guanabenz; D013890:Thiourea