title: Autophagy-dependent rhodopsin degradation prevents retinal degeneration in Drosophila.
abstract: Recent studies have demonstrated protective roles for autophagy in various neurodegenerative disorders, including the polyglutamine diseases; however, the role of autophagy in retinal degeneration has remained unclear. Accumulation of activated rhodopsin in some Drosophila mutants leads to retinal degeneration, and although it is known that activated rhodopsin is degraded in endosomal pathways in normal photoreceptor cells, the contribution of autophagy to rhodopsin regulation has remained elusive. This study reveals that activated rhodopsin is degraded by autophagy in collaboration with endosomal pathways to prevent retinal degeneration. Light-dependent retinal degeneration in the Drosophila visual system is caused by the knockdown or mutation of autophagy-essential components, such as autophagy-related protein 7 and 8 (atg-7/atg-8), or genes essential for PE (phosphatidylethanolamine) biogenesis and autophagosome formation, including Phosphatidylserine decarboxylase (Psd) and CDP-ethanolamine:diacylglycerol ethanolaminephosphotransferase (Ept). The knockdown of atg-7/8 or Psd/Ept produced an increase in the amount of rhodopsin localized to Rab7-positive late endosomes. This rhodopsin accumulation, followed by retinal degeneration, was suppressed by overexpression of Rab7, which accelerated the endosomal degradation pathway. These results indicate a degree of cross talk between the autophagic and endosomal/lysosomal pathways. Importantly, a reduction in rhodopsin levels rescued Psd knockdown-induced retinal degeneration. Additionally, the Psd knockdown-induced retinal degeneration phenotype was enhanced by Ppt1 inactivation, which causes infantile neuronal ceroid lipofuscinosis, implying that autophagy plays a significant role in its pathogenesis. Collectively, the current data reveal that autophagy suppresses light-dependent retinal degeneration in collaboration with the endosomal degradation pathway and that rhodopsin is a key substrate for autophagic degradation in this context.
authors: Research Group of Glycobiology and Glycotechnology, Mutant Flies Laboratory, Mitsubishi-Kagaku Institute of Life Sciences, Machida 194-8511, Japan.
authors: Ryosuke
authors: R
authors: Midorikawa
authors: Miki
authors: M
authors: Yamamoto-Hino
authors: Wakae
authors: W
authors: Awano
authors: Yoshimi
authors: Y
authors: Hinohara
authors: Emiko
authors: E
authors: Suzuki
authors: Ryu
authors: R
authors: Ueda
authors: Satoshi
authors: S
authors: Goto
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001343:Autophagy / Q000502:physiology*; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism / Q000648:ultrastructure; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D020287:In Situ Nick-End Labeling / Q000379:methods; D007814:Larva; D008027:Light / Q000009:adverse effects; D008247:Lysosomes / Q000378:metabolism / Q000648:ultrastructure; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D046529:Microscopy, Electron, Transmission / Q000379:methods; D016253:Microscopy, Immunoelectron / Q000379:methods; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D017956:Photoreceptor Cells, Invertebrate / Q000378:metabolism* / Q000648:ultrastructure; D034622:RNA Interference / Q000502:physiology; D012162:Retinal Degeneration / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D012243:Rhodopsin / Q000235:genetics / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013869:Thiolester Hydrolases; D013997:Time Factors; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D029721:Drosophila Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000090802:rab7 GTP-Binding Proteins; D049452:Green Fluorescent Proteins; D012243:Rhodopsin; D013869:Thiolester Hydrolases; C498814:Ppt1 protein, Drosophila; D020691:rab GTP-Binding Proteins