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Proteopathy Linked to Exon-Skipping Isoform of RGR-Opsin Contributes to the Pathogenesis of Age-Related Macular Degeneration

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机构: [1]Department of Ophthalmology, Eye Disease and Optometry Institute, Peking University People's Hospital, Beijing, China. [2]Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, Beijing, China. [3]Department of Ophthalmology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China. [4]Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States. [5]Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine of University of Southern California, Los Angeles, California, United States. [6]Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California, United States.
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关键词: age-related macular degeneration drusen retinal pigment epithelium RGR-d proteopathy endoplasmic reticulum stress

摘要:
Proteopathy is believed to contribute to age-related macular degeneration (AMD). Much research indicates that AMD begins in the retinal pigment epithelium (RPE), which is associated with formation of extracellular drusen, a clinical hallmark of AMD. Human RPE produces a drusen-associated abnormal protein, the exon Ⅵ-skipping splice isoform of retinal G protein-coupled receptor (RGR-d). In this study, we investigate the detrimental effects of RGR-d on cultured cells and mouse retina.ARPE-19 cells were stably infected by lentivirus overexpressing RGR or RGR-d and were treated with MG132, sometimes combined with or without endoplasmic reticulum (ER) stress inducer, tunicamycin. RGR and RGR-d protein expression, degeneration pathway, and potential cytotoxicity were explored. Homozygous RGR-d mice aged 8 or 14 months were fed with a high-fat diet for 3 months and then subjected to ocular examination and histopathology experiments.We confirm that RGR-d is proteotoxic under various conditions. In ARPE-19 cells, RGR-d is misfolded and almost completely degraded via the ubiquitin-proteasome system. Unlike normal RGR, RGR-d increases ER stress, triggers the unfolded protein response, and exerts potent cytotoxicity. Aged RGR-d mice manifest disrupted RPE cell integrity, apoptotic photoreceptors, choroidal deposition of complement C3, and CD86+CD32+ proinflammatory cell infiltration into retina and RPE-choroid. Furthermore, the AMD-like phenotype of RGR-d mice can be aggravated by a high-fat diet.Our study confirmed the pathogenicity of the RGR splice isoform and corroborated a significant role of proteopathy in AMD. These findings may contribute to greater comprehension of the multifactorial causes of AMD.

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出版当年[2022]版:
大类 | 2 区 医学
小类 | 2 区 眼科学
最新[2023]版:
大类 | 2 区 医学
小类 | 2 区 眼科学
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出版当年[2021]版:
Q1 OPHTHALMOLOGY
最新[2023]版:
Q1 OPHTHALMOLOGY

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第一作者机构: [1]Department of Ophthalmology, Eye Disease and Optometry Institute, Peking University People's Hospital, Beijing, China. [2]Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, Beijing, China.
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通讯机构: [1]Department of Ophthalmology, Eye Disease and Optometry Institute, Peking University People's Hospital, Beijing, China. [2]Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, Beijing, China. [5]Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine of University of Southern California, Los Angeles, California, United States. [6]Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California, United States. [*1]Department of Ophthalmology, KeckSchool of Medicine of University ofSouthern California, Mudd MemorialResearch Bldg, MMR-322, 1333 SanPablo St., Los Angeles, CA 90089,USA [*2]Department of Ophthalmology, Eye Disease andOptometry Institute, PekingUniversity People’s Hospital, Beijing,China [*3]Beijing Key Laboratory of Diagnosis and Therapy of Retinaland Choroid Diseases, Beijing,China [*4]Xizhimen South Street 11, XiCheng District, Beijing 100044,China
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