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.北京朝阳医院[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.
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.
基金:
Supported by the National Natural Science Foundation of China(NSFC No. 82171060) and the National Key R&D Program ofChina (No. 2020YFC2008200).
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.
共同第一作者:
通讯作者:
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
推荐引用方式(GB/T 7714):
Ren Chi,Cui Haoran,Bao Xuan,et al.Proteopathy Linked to Exon-Skipping Isoform of RGR-Opsin Contributes to the Pathogenesis of Age-Related Macular Degeneration[J].INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE.2023,64(13):41.doi:10.1167/iovs.64.13.41.
APA:
Ren Chi,Cui Haoran,Bao Xuan,Huang Lvzhen,He Shikun...&Zhao Mingwei.(2023).Proteopathy Linked to Exon-Skipping Isoform of RGR-Opsin Contributes to the Pathogenesis of Age-Related Macular Degeneration.INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE,64,(13)
MLA:
Ren Chi,et al."Proteopathy Linked to Exon-Skipping Isoform of RGR-Opsin Contributes to the Pathogenesis of Age-Related Macular Degeneration".INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 64..13(2023):41