Di-retinoid-pyridinium-ethanolamine (A2E) Accumulation and the Maintenance of the Visual Cycle Are Independent of Atg7-mediated Autophagy in the Retinal Pigmented Epithelium

Perusek, Lindsay; Sahu, Bhubanananda; Parmar, Tanu; Maeno, Hiroshi; Arai, Eisuke; Le, Yun Zheng; Subauste, Carlos S.; Chen, Yu; Palczewski, Krzysztof; Maeda, Akiko

doi:10.1074/jbc.m115.682310

Cited by 31 publications

(26 citation statements)

References 59 publications

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“…At the protein level, presence of Atg7 in the RPE of wild-type mice has previously been reported [ 22 ], however, in the present study the amounts of Atg7 in the RPE were below the detection limits of our well-established Western blot assay [ 31 ]. Because of this limitation, the downstream effects of Atg7 deletion, that is, the accumulation of autophagy substrates, had to be used as indicator of suppressed autophagy in target cells.…”

Section: Resultscontrasting

confidence: 68%

“…The RPE-specific deletion of the autophagy gene Atg5 diminished the phagocytosis and degradation of photoreceptor outer segments [ 21 ], suggesting that components of the molecular machinery of autophagy are involved in the maintenance of normal vision. Recently, Atg7 was deleted in an inducible and RPE-specific manner using mice that carry Atg7 flanked by loxP sites, Cre under the control of the tetracycline-responsive element (TRE) and a transgenic reverse tetracycline-dependent transactivator (rtTA) gene driven by the RPE-specific human vitelliform macular dystrophy-2 ( VMD2 ) promoter [ 22 ]. In contrast to RPE lacking Atg5 [ 21 ], deletion of Atg7 did not reduce levels of 11- cis -retinal [ 22 ], indicating differences in the functions of Atg5 and Atg7 in non-canonical autophagy-related processes and/or effects of the genetic background of the different mouse models [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

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Tyrosinase-Cre-Mediated Deletion of the Autophagy Gene Atg7 Leads to Accumulation of the RPE65 Variant M450 in the Retinal Pigment Epithelium of C57BL/6 Mice

et al. 2016

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Targeted gene knockout mouse models have helped to identify roles of autophagy in many tissues. Here, we investigated the retinal pigment epithelium (RPE) of Atg7f/f Tyr-Cre mice (on a C57BL/6 background), in which Cre recombinase is expressed under the control of the tyrosinase promoter to delete the autophagy gene Atg7. In line with pigment cell-directed blockade of autophagy, the RPE and the melanocytes of the choroid showed strong accumulation of the autophagy adaptor and substrate, sequestosome 1 (Sqstm1)/p62, relative to the levels in control mice. Immunofluorescence and Western blot analysis demonstrated that the RPE, but not the choroid melanocytes, of Atg7f/f Tyr-Cre mice also had strongly increased levels of retinoid isomerohydrolase RPE65, a pivotal enzyme for the maintenance of visual perception. In contrast to Sqstm1, genes involved in retinal regeneration, i.e. Lrat, Rdh5, Rgr, and Rpe65, were expressed at higher mRNA levels. Sequencing of the Rpe65 gene showed that Atg7f/f and Atg7f/f Tyr-Cre mice carry a point mutation (L450M) that is characteristic for the C57BL/6 mouse strain and reportedly causes enhanced degradation of the RPE65 protein by an as-yet unknown mechanism. These results suggest that the increased abundance of RPE65 M450 in the RPE of Atg7f/f Tyr-Cre mice is, at least partly, mediated by upregulation of Rpe65 transcription; however, our data are also compatible with the hypothesis that the RPE65 M450 protein is degraded by Atg7-dependent autophagy in Atg7f/f mice. Further studies in mice of different genetic backgrounds are necessary to determine the relative contributions of these mechanisms.

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Section: Resultscontrasting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Tyrosinase-Cre-Mediated Deletion of the Autophagy Gene Atg7 Leads to Accumulation of the RPE65 Variant M450 in the Retinal Pigment Epithelium of C57BL/6 Mice

et al. 2016

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“…In the retina, autophagy plays an important role in cellular metabolism [16] and in preventing light-induced retinal damage in photoreceptors [17]. Deficiency of the autophagy regulatory gene, Atg7, results in light-induced retinal degeneration [18] or RPE degeneration [19] in mice. The inhibiting function of the macroautophagy gene, Atg5, results in both cone [20] and rod dysfunction [21].…”

Section: Discussionmentioning

confidence: 99%

Clinical Course and Electron Microscopic Findings in Lymphocytes of Patients with DRAM2-Associated Retinopathy

Kuniyoshi

Hayashi

Kameya

et al. 2020

IJMS

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DRAM2-associated retinopathy is a rare inherited retinal dystrophy, and its outcome has not been determined. A single retinal involvement by a mutation of the DRAM2 gene is unexplained. We found three unrelated patients with a disease-causing DRAM2 variant in a biallelic state from 1555 Japanese individuals of 1314 families with inherited retinal dystrophy. We reviewed their medical records and examined their peripheral lymphocytes by transmission electron microscopy (TEM). Patient 1 was a 38-year-old woman who complained of night blindness and reduced vision. She developed macular degeneration at age 43 years. Patients 2 and 3 were a man and a woman both of whom noticed night blindness in their 30s. Both had a degeneration in the macula and midperiphery in their 40s, which progressed to a diffuse retinal degeneration in their 60s when their vision was reduced to hand motions. Three novel DRAM2 variants were identified. TEM of the lymphocytes of Patients 1 and 2 showed abnormal structures in 40.6% and 0.3% of the peripheral lymphocytes, respectively. We concluded that the DRAM2-associated retinopathy of our patients was a progressive rod-cone dystrophy, and the visual outcome was poor. The systemic effect of DRAM2 mutations may be compensable and have variations.

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“…A2E probably activates autophagy through the Akt/ mTOR signaling pathway [97,98]. During this process, the Atg7-mediated pathway is not required [99]. Here, autophagy plays an important role in protecting RPE cells from the accumulation of toxic debris.…”

Section: Corneal Dystrophymentioning

confidence: 99%

Autophagy and Age-Related Eye Diseases

Yang

Pan

Zhao

et al. 2019

BioMed Research International

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Background. Autophagy is a catabolic process that depends on the lysosome. It is usually used to maintain cellular homeostasis, survival and development by degrading abnormal substances and dysfunctional organelles, especially when the cell is exposed to starvation or other stresses. Increasing studies have reported that autophagy is associated with various eye diseases, of which aging is one of the important factors. Objective. To summarize the functional and regulatory role of autophagy in ocular diseases with aging, and discuss the possibility of autophagy-targeted therapy in age-related diseases. Methods. PubMed searches were performed to identify relevant articles published mostly in the last 5 years. The key words were used to retrieve including “autophagy”, “aging”, “oxidative stress AND autophagy”, “dry eye AND autophagy”, “corneal disease AND autophagy”, “glaucoma AND autophagy”, “cataract AND autophagy”, “AMD AND autophagy”, “cardiovascular diseases AND autophagy”, “diabetes AND autophagy”. After being classified and assessed, the most relevant full texts in English were chosen. Results. Apart from review articles, more than two research articles for each age-related eye diseases related to autophagy were retrieved. We only included the most relevant and recent studies for summary and discussion. Conclusion. Autophagy has both protective and detrimental effects on the progress of age-related eye diseases. Different types of studies based on certain situations in vitro showed distinct results, which do not necessarily coincide with the actual situation in human bodies completely. It means the exact role and regulatory function of autophagy in ocular diseases remains largely unknown. Although autophagy as a potential therapeutic target has been proposed, many problems still need to be solved before it applies to clinical practice.

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Di-retinoid-pyridinium-ethanolamine (A2E) Accumulation and the Maintenance of the Visual Cycle Are Independent of Atg7-mediated Autophagy in the Retinal Pigmented Epithelium

Cited by 31 publications

References 59 publications

Tyrosinase-Cre-Mediated Deletion of the Autophagy Gene Atg7 Leads to Accumulation of the RPE65 Variant M450 in the Retinal Pigment Epithelium of C57BL/6 Mice

Tyrosinase-Cre-Mediated Deletion of the Autophagy Gene Atg7 Leads to Accumulation of the RPE65 Variant M450 in the Retinal Pigment Epithelium of C57BL/6 Mice

Clinical Course and Electron Microscopic Findings in Lymphocytes of Patients with DRAM2-Associated Retinopathy

Autophagy and Age-Related Eye Diseases

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