Caenorhabditis elegans RNA-processing protein TDP-1 regulates protein homeostasis and life span.
Transactive response DNA-binding protein (TARDBP/TDP-43), a heterogeneous nuclear ribonucleoprotein (hnRNP) with diverse activities, is a common denominator in several neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Orthologs of TDP-43 exist in animals ranging from mammals to invertebrates. Here, we systematically studied mutant Caenorhabditis elegans lacking the nematode TDP-43 ortholog, TDP-1. Heterologous expression of human TDP-43 rescued the defects in C. elegans lacking TDP-1, suggesting their functions are conserved. Although the tdp-1 mutants exhibited deficits in fertility, growth, and locomotion, loss of tdp-1 attenuated defects in several C. elegans models of proteotoxicity. Loss of tdp-1 suppressed defects in transgenic C. elegans expressing TDP-43 or CuZn superoxide dismutase, both of which are associated with proteotoxicity in neurodegenerative diseases. Loss of tdp-1 also reduced defects in mutant animals lacking the heat shock factor HSF-1. Transcriptional profiling demonstrated that the loss of TDP-1 altered expression of genes functioning in RNA processing and protein folding. Furthermore, the absence of tdp-1 extended the life span in C. elegans. The life span extension required a FOXO transcriptional factor DAF-16 but not HSF-1. These results suggest that the C. elegans TDP-1 has a role in the regulation of protein homeostasis and aging.
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University School of Medicine, Baltimore, Maryland 212105, USA.
Tao
T
Zhang
Ho-Yon
HY
Hwang
Haiping
H
Hao
Conover
C
Talbot
Jiou
J
Wang
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D051858:Forkhead Transcription Factors; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000378:metabolism; D005816:Genetic Complementation Test; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D008136:Longevity / Q000502:physiology*; D009154:Mutation; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; C474710:heat shock factor-1, C elegans