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

• DOI: 10.1371/journal.pgen.1002806
• Publication Date: 2012-07-06T01:26:51Z
• Authors: Alexandra Vaccaro; Arnaud Tauffenberger; Peter E. A. Ash; Yari Carlomagno; Leonard Petrucelli; J. Alex Parker
• Keywords: Proteotoxicity; Stress granule

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 abnormal pathological role of this protein, we turned Caenorhabditis elegans its orthologue TDP-1. We report that TDP-1 functions in Insulin/IGF pathway regulate longevity oxidative stress response downstream from forkhead transcription factor DAF-16/FOXO3a. However, although tdp-1 mutants are stress-sensitive, chronic upregulation expression toxic decreases lifespan. ALS–associated mutations or related RNA FUS activate unfolded generate leading daf-16–dependent with negative effects on neuronal function Consistently, deletion endogenous rescues mutant proteotoxicity C. elegans. These results suggest induction wild-type TDP-1/TDP-43 by cellular may propagate neurodegeneration decrease