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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.
AuthorsRyosuke Midorikawa, Miki Yamamoto-Hino, Wakae Awano, Yoshimi Hinohara, Emiko Suzuki, Ryu Ueda, Satoshi Goto
JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 30 Issue 32 Pg. 10703-19 (Aug 11 2010) ISSN: 1529-2401 [Electronic] United States
PMID20702701 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Drosophila Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Ppt1 protein, Drosophila
  • Green Fluorescent Proteins
  • rab7 protein
  • Rhodopsin
  • rab GTP-Binding Proteins
Topics
  • Animals
  • Animals, Genetically Modified
  • Autophagy (physiology)
  • Disease Models, Animal
  • Drosophila
  • Drosophila Proteins (genetics, metabolism)
  • Endosomes (metabolism, ultrastructure)
  • Gene Expression Regulation (genetics, physiology)
  • Green Fluorescent Proteins (genetics)
  • In Situ Nick-End Labeling (methods)
  • Larva
  • Light (adverse effects)
  • Lysosomes (metabolism, ultrastructure)
  • Membrane Proteins (genetics, metabolism)
  • Microscopy, Electron, Transmission (methods)
  • Microscopy, Immunoelectron (methods)
  • Mutation (genetics)
  • Nerve Tissue Proteins (genetics, metabolism)
  • Photoreceptor Cells, Invertebrate (metabolism, ultrastructure)
  • RNA Interference (physiology)
  • Retinal Degeneration (etiology, genetics, prevention & control)
  • Rhodopsin (genetics, metabolism)
  • Statistics, Nonparametric
  • Time Factors
  • rab GTP-Binding Proteins (metabolism)

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