PMID- 20702701 OWN - NLM STAT- MEDLINE DCOM- 20100903 LR - 20211203 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 30 IP - 32 DP - 2010 Aug 11 TI - Autophagy-dependent rhodopsin degradation prevents retinal degeneration in Drosophila. PG - 10703-19 LID - 10.1523/JNEUROSCI.2061-10.2010 [doi] AB - 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. FAU - Midorikawa, Ryosuke AU - Midorikawa R AD - Research Group of Glycobiology and Glycotechnology, Mutant Flies Laboratory, Mitsubishi-Kagaku Institute of Life Sciences, Machida 194-8511, Japan. FAU - Yamamoto-Hino, Miki AU - Yamamoto-Hino M FAU - Awano, Wakae AU - Awano W FAU - Hinohara, Yoshimi AU - Hinohara Y FAU - Suzuki, Emiko AU - Suzuki E FAU - Ueda, Ryu AU - Ueda R FAU - Goto, Satoshi AU - Goto S LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Drosophila Proteins) RN - 0 (Membrane Proteins) RN - 0 (Nerve Tissue Proteins) RN - 0 (rab7 GTP-Binding Proteins) RN - 147336-22-9 (Green Fluorescent Proteins) RN - 9009-81-8 (Rhodopsin) RN - EC 3.1.2.- (Thiolester Hydrolases) RN - EC 3.1.2.22 (Ppt1 protein, Drosophila) RN - EC 3.6.5.2 (rab GTP-Binding Proteins) SB - IM MH - Animals MH - Animals, Genetically Modified MH - Autophagy/*physiology MH - Disease Models, Animal MH - Drosophila MH - Drosophila Proteins/genetics/metabolism MH - Endosomes/metabolism/ultrastructure MH - Gene Expression Regulation/genetics/physiology MH - Green Fluorescent Proteins/genetics MH - In Situ Nick-End Labeling/methods MH - Larva MH - Light/adverse effects MH - Lysosomes/metabolism/ultrastructure MH - Membrane Proteins/genetics/metabolism MH - Microscopy, Electron, Transmission/methods MH - Microscopy, Immunoelectron/methods MH - Mutation/genetics MH - Nerve Tissue Proteins/genetics/metabolism MH - Photoreceptor Cells, Invertebrate/*metabolism/ultrastructure MH - RNA Interference/physiology MH - Retinal Degeneration/etiology/genetics/*prevention & control MH - Rhodopsin/genetics/*metabolism MH - Statistics, Nonparametric MH - Thiolester Hydrolases MH - Time Factors MH - rab GTP-Binding Proteins/metabolism MH - rab7 GTP-Binding Proteins PMC - PMC6634698 EDAT- 2010/08/13 06:00 MHDA- 2010/09/04 06:00 PMCR- 2011/02/11 CRDT- 2010/08/13 06:00 PHST- 2010/08/13 06:00 [entrez] PHST- 2010/08/13 06:00 [pubmed] PHST- 2010/09/04 06:00 [medline] PHST- 2011/02/11 00:00 [pmc-release] AID - 30/32/10703 [pii] AID - 3620329 [pii] AID - 10.1523/JNEUROSCI.2061-10.2010 [doi] PST - ppublish SO - J Neurosci. 2010 Aug 11;30(32):10703-19. doi: 10.1523/JNEUROSCI.2061-10.2010.