title: Autophagy protects the retina from light-induced degeneration.
abstract: Autophagy is a conserved feature of lysosome-mediated intracellular degradation. Dysregulated autophagy is implicated as a contributor in neurodegenerative diseases; however, the role of autophagy in retinal degeneration remains largely unknown. Here, we report that the photo-activated visual chromophore, all-trans-retinal, modulated autophagosome formation in ARPE19 retinal cells. Increased formation of autophagosomes in these cells was observed when incubated with 2.5 μM all-trans-retinal, a condition that did not cause cell death after 24 h in culture. However, autophagosome formation was decreased at concentrations, which caused cell death. Increased expression of activating transcription factor 4 (Atf4), which indicates the activation of oxidative stress, was recorded in response to light illumination in retinas of Abca4(-/-)Rdh8(-/-) mice, which showed delayed clearance of all-trans-retinal after light exposure. Expression of autophagosome marker LC3B-II and mitochondria-specific autophagy, mitophagy, regulator Park2, were significantly increased in the retinas of Abca4(-/-)Rdh8(-/-) mice after light exposure, suggesting involvement of autophagy and mitophagy in the pathogenesis of light-induced retinal degeneration. Deletion of essential genes required for autophagy, including Beclin1 systemically or Atg7 in only rod photoreceptors resulted in increased susceptibility to light-induced retinal damage. Increased photoreceptor cell death was observed when retinas lacking the rod photoreceptor-specific Atg7 gene were coincubated with 20 μM all-trans-retinal. Park2(-/-) mice also displayed light-induced retinal degeneration. Ultra-structural analyses showed mitochondrial and endoplasmic reticulum impairment in retinas of these model animals after light exposure. Taken together, these observations provide novel evidence implicating an important role of autophagy and mitophagy in protecting the retina from all-trans-retinal- and light-induced degeneration.
authors: Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106; Yueyang Hospital and Clinical Research Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
authors: Yu
authors: Y
authors: Chen
authors: Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio 44106.
authors: Osamu
authors: O
authors: Sawada
authors: Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106.
authors: Hideo
authors: H
authors: Kohno
authors: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 43104.
authors: Yun-Zheng
authors: YZ
authors: Le
authors: Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
authors: Carlos
authors: C
authors: Subauste
authors: Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106; Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio 44106.
authors: Tadao
authors: T
authors: Maeda
authors: Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106; Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio 44106. Electronic address: aam19@case.edu.
authors: Akiko
authors: A
authors: Maeda
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000429:Alcohol Oxidoreductases / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D000071186:Beclin-1; D016923:Cell Death; D002460:Cell Line; D006801:Humans; D008027:Light; D008247:Lysosomes / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010775:Photic Stimulation / Q000009:adverse effects; D012160:Retina / Q000378:metabolism*; D012162:Retinal Degeneration / Q000378:metabolism; D012243:Rhodopsin / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D000426:Alcohol Dehydrogenase; D000429:Alcohol Oxidoreductases; D051017:Apoptosis Regulatory Proteins; D000071193:Autophagy-Related Protein 7; D000071186:Beclin-1; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D012243:Rhodopsin; D044764:Ubiquitin-Activating Enzymes; D044767:Ubiquitin-Protein Ligases; D014801:Vitamin A; C056475:ABCA4 protein, human; C512841:Abca4 protein, mouse; C502661:Atg7 protein, mouse; C491997:BECN1 protein, human; C115010:Becn1 protein, mouse; C525880:HSD17B6 protein, mouse; C022520:retinol dehydrogenase; C111567:parkin protein; C509349:ATG7 protein, human