TDP-1/TDP-43 Regulates Stress Signaling and Age-Dependent Proteotoxicity in Caenorhabditis elegans

TDP-43 is a multifunctional nucleic acid binding protein linked to several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia. To learn more about the normal biological and abnormal pathological role of this protein, we turned to Caenorhabditis elegans and its orthologue TDP-1. We report that TDP-1 functions in the Insulin/IGF pathway to regulate longevity and the oxidative stress response downstream from the forkhead transcription factor DAF-16/FOXO3a. However, although tdp-1 mutants are stress-sensitive, chronic upregulation of tdp-1 expression is toxic and decreases lifespan. ALS–associated mutations in TDP-43 or the related RNA binding protein FUS activate the unfolded protein response and generate oxidative stress leading to the daf-16–dependent upregulation of tdp-1 expression with negative effects on neuronal function and lifespan. Consistently, deletion of endogenous tdp-1 rescues mutant TDP-43 and FUS proteotoxicity in C. elegans. These results suggest that chronic induction of wild-type TDP-1/TDP-43 by cellular stress may propagate neurodegeneration and decrease lifespan.
Author Summary TAR DNA Binding Protein 43 (TDP-43) is implicated in several human age-dependent neurodegenerative disorders, but until now little was known about TDP-43's role in the aging process. Here we used the nematode Caenorhabditis elegans to study the role of the TDP-43 orthologue tdp-1 in aging and neurodegeneration. In this study we discovered that tdp-1 is a stress-responsive gene acting within the Insulin/IGF signaling pathway to regulate lifespan and the response to oxidative stress. We found that, although worms missing tdp-1 were stress-sensitive, elevated expression of tdp-1 was toxic. We asked if tdp-1 also responded to the stress caused by toxic proteins found in Amyotrophic Lateral Sclerosis (ALS). Using worm models for ALS, we discovered that mutant TDP-43 generated oxidative stress and induced tdp-1 expression with negative consequences on neuronal function and lifespan. Consistently, removing tdp-1 rescued toxicity in our worm ALS models. tdp-1's role in the cellular stress response likely reflects an ancient adaptation to deal with unfavorable environmental conditions that is inappropriately activated and maintained by genetic mutations leading to proteotoxic and oxidative stress. We predict that similar mechanisms may exist in humans, helping explain the involvement of TDP-43 in a growing number of neurodegenerative disorders.