CRCHUM, Université de Montréal, Montréal, Québec, Canada.
PLoS Genet. 2012 Jul;8(7):e1002806. doi: 10.1371/journal.pgen.1002806. Epub 2012 Jul 5.
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.
TDP-43 是一种多功能核酸结合蛋白，与包括肌萎缩性侧索硬化症（ALS）和额颞叶痴呆在内的几种神经退行性疾病有关。为了更多地了解该蛋白的正常生物学和异常病理作用，我们转向秀丽隐杆线虫及其直系同源物 TDP-1。我们报告称，TDP-1 在胰岛素/IGF 途径中发挥作用，以调节长寿和叉头转录因子 DAF-16/FOXO3a 下游的氧化应激反应。然而，尽管 tdp-1 突变体对压力敏感，但 tdp-1 表达的慢性上调是有毒的，并缩短寿命。TDP-43 或相关 RNA 结合蛋白 FUS 的 ALS 相关突变激活未折叠蛋白反应并产生氧化应激，导致 daf-16 依赖性 tdp-1 表达上调，对神经元功能和寿命产生负面影响。一致地，秀丽隐杆线虫中内源性 tdp-1 的缺失挽救了突变型 TDP-43 和 FUS 的毒性。这些结果表明，细胞应激引起的野生型 TDP-1/TDP-43 的慢性诱导可能会促进神经退行性变并缩短寿命。
