TOR-mediated autophagy regulates cell death in Drosophila neurodegenerative disease.
Target of rapamycin (TOR) signaling is a regulator of cell growth. TOR activity can also enhance cell death, and the TOR inhibitor rapamycin protects cells against proapoptotic stimuli. Autophagy, which can protect against cell death, is negatively regulated by TOR, and disruption of autophagy by mutation of Atg5 or Atg7 can lead to neurodegeneration. However, the implied functional connection between TOR signaling, autophagy, and cell death or degeneration has not been rigorously tested. Using the Drosophila melanogaster visual system, we show in this study that hyperactivation of TOR leads to photoreceptor cell death in an age- and light-dependent manner and that this is because of TOR's ability to suppress autophagy. We also find that genetically inhibiting TOR or inducing autophagy suppresses cell death in Drosophila models of Huntington's disease and phospholipase C (norpA)-mediated retinal degeneration. Thus, our data indicate that TOR induces cell death by suppressing autophagy and provide direct genetic evidence that autophagy alleviates cell death in several common types of neurodegenerative disease.
Wang
Tao
T
Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Lao
Uyen
U
Edgar
Bruce A
BA
D000818:Animals; D030801:Animals, Genetically Modified; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D000071189:Autophagy-Related Protein-1 Homolog; D016923:Cell Death / Q000502:physiology*; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000502:physiology; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000473:pathology / Q000503:physiopathology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D017956:Photoreceptor Cells, Invertebrate / Q000378:metabolism / Q000648:ultrastructure; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases
D000071193:Autophagy-Related Protein 7; D000071189:Autophagy-Related Protein-1 Homolog; D029721:Drosophila Proteins; D020559:Monomeric GTP-Binding Proteins; D009479:Neuropeptides; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D000076205:Ras Homolog Enriched in Brain Protein; D058570:TOR Serine-Threonine Kinases; C530193:Atg7 protein, Drosophila; C490212:Rheb protein, Drosophila; C416303:target of rapamycin protein, Drosophila; C518074:Atg1 protein, Drosophila