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Published online
doi:10.1083/jcb.200904090
The Journal of Cell Biology, Vol. 186, No. 5, 703-711
The Rockefeller University Press, 0021-9525 $30.00
© Wang et al.
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TOR-mediated autophagy regulates cell death in Drosophila neurodegenerative disease



Tao Wang, Uyen Lao, and Bruce A. Edgar

Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109

Correspondence to Bruce A. Edgar: bedgar{at}fhcrc.org

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.

Abbreviations used in this paper: 4EBP, eukaryotic initiation factor 4E–binding protein; GMR, glass multiple reporter; HD, Huntington' disease; PI3K, phosphatidylinositol 3 kinase; polyQ, polyglutamine; PTEN, phosphatase and tensin homologue; Rheb, Ras homologue enriched in brain protein; S6K, P70 ribosomal S6 kinase; TOR, target of rapamycin; TSC, tuberous sclerosis complex; UAS, upstream activator sequence.

© 2009 Wang et al.
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