JNK/FOXO-mediated neuronal expression of fly homologue of peroxiredoxin II reduces oxidative stress and extends life span.
Activation of c-Jun N-terminal kinase (JNK) signaling in neurons increases stress resistance and extends life span, in part through FOXO-mediated transcription in Drosophila. However, the JNK/FOXO target genes are unknown. Here, we identified Jafrac1, a Drosophila homolog of human Peroxiredoxin II (hPrxII), as a downstream effecter of JNK/FOXO signaling in neurons that enhances stress resistance and extends life span. We found that Jafrac1 was expressed in the adult brain and induced by paraquat, a reactive oxygen species-generating chemical. RNA interference-mediated neuronal knockdown of Jafrac1 enhanced, while neuronal overexpression of Jafrac1 and hPrxII suppressed, paraquat-induced lethality in flies. Neuronal expression of Jafrac1 also significantly reduced ROS levels, restored mitochondrial function, and attenuated JNK activation caused by paraquat. Activation of JNK/FOXO signaling in neurons increased the Jafrac1 expression level under both normal and oxidative stressed conditions. Moreover, neuronal knockdown of Jafrac1 shortened, while overexpression of Jafrac1 and hPrxII extended, the life span in flies. These results support the hypothesis that JNK/FOXO signaling extends life span via amelioration of oxidative damage and mitochondrial dysfunction in neurons.
Lee
Kyu-Sun
KS
Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea.
Iijima-Ando
Kanae
K
Iijima
Koichi
K
Lee
Won-Jae
WJ
Lee
Joon H
JH
Yu
Kweon
K
Lee
Dong-Seok
DS
D000818:Animals; D001921:Brain / Q000201:enzymology; D029721:Drosophila Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006540:Herbicides / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008136:Longevity / Q000187:drug effects / Q000502:physiology*; D008928:Mitochondria / Q000201:enzymology; D009474:Neurons / Q000201:enzymology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010269:Paraquat / Q000494:pharmacology; D010544:Peroxidases / Q000096:biosynthesis* / Q000235:genetics; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D006540:Herbicides; D017382:Reactive Oxygen Species; C404709:Jafrac1 protein, Drosophila; D010544:Peroxidases; C515940:PRDX1 protein, human; D054464:Peroxiredoxins; D048031:JNK Mitogen-Activated Protein Kinases; D010269:Paraquat