Pgc-1α repression and high-fat diet induce age-related macular degeneration-like phenotypes in mice
Age-related macular degeneration (AMD) is the major cause of blindness in the elderly in developed countries and its prevalence is increasing with the aging population. AMD initially affects the retinal pigment epithelium (RPE) and gradually leads to secondary photoreceptor degeneration. Recent stud...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2018-09-01
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| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/11/9/dmm032698 |
| _version_ | 1811198736413491200 |
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| author | Meng Zhang Yi Chu Joseph Mowery Brandon Konkel Susana Galli Alexander C. Theos Nady Golestaneh |
| author_facet | Meng Zhang Yi Chu Joseph Mowery Brandon Konkel Susana Galli Alexander C. Theos Nady Golestaneh |
| author_sort | Meng Zhang |
| collection | DOAJ |
| description | Age-related macular degeneration (AMD) is the major cause of blindness in the elderly in developed countries and its prevalence is increasing with the aging population. AMD initially affects the retinal pigment epithelium (RPE) and gradually leads to secondary photoreceptor degeneration. Recent studies have associated mitochondrial damage with AMD, and we have observed mitochondrial and autophagic dysfunction and repressed peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α; also known as Ppargc1a) in native RPE from AMD donor eyes and their respective induced pluripotent stem cell-derived RPE. To further investigate the effect of PGC-1α repression, we have established a mouse model by feeding Pgc-1α+/− mice with a high-fat diet (HFD) and investigated RPE and retinal health. We show that when mice expressing lower levels of Pgc-1α are exposed to HFD, they present AMD-like abnormalities in RPE and retinal morphology and function. These abnormalities include basal laminar deposits, thickening of Bruch's membrane with drusen marker-containing deposits, RPE and photoreceptor degeneration, decreased mitochondrial activity, increased levels of reactive oxygen species, decreased autophagy dynamics/flux, and increased inflammatory response in the RPE and retina. Our study shows that Pgc-1α is important in outer retina biology and that Pgc-1α+/− mice fed with HFD provide a promising model to study AMD, opening doors for novel treatment strategies. |
| first_indexed | 2024-04-12T01:35:16Z |
| format | Article |
| id | doaj.art-6d060bb8e2d64b36b6825df7921ec440 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-04-12T01:35:16Z |
| publishDate | 2018-09-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-6d060bb8e2d64b36b6825df7921ec4402022-12-22T03:53:20ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112018-09-0111910.1242/dmm.032698032698Pgc-1α repression and high-fat diet induce age-related macular degeneration-like phenotypes in miceMeng Zhang0Yi Chu1Joseph Mowery2Brandon Konkel3Susana Galli4Alexander C. Theos5Nady Golestaneh6 Department of Ophthalmology, Georgetown University Medical Center, Washington, DC 20057, USA Department of Ophthalmology, Georgetown University Medical Center, Washington, DC 20057, USA Electron and Confocal Microscopy Unit, USDA Agricultural Research Service, Beltsville, MD 20705, USA Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA Department of Human Science, Georgetown University, Washington, DC 20057, USA Department of Ophthalmology, Georgetown University Medical Center, Washington, DC 20057, USA Age-related macular degeneration (AMD) is the major cause of blindness in the elderly in developed countries and its prevalence is increasing with the aging population. AMD initially affects the retinal pigment epithelium (RPE) and gradually leads to secondary photoreceptor degeneration. Recent studies have associated mitochondrial damage with AMD, and we have observed mitochondrial and autophagic dysfunction and repressed peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α; also known as Ppargc1a) in native RPE from AMD donor eyes and their respective induced pluripotent stem cell-derived RPE. To further investigate the effect of PGC-1α repression, we have established a mouse model by feeding Pgc-1α+/− mice with a high-fat diet (HFD) and investigated RPE and retinal health. We show that when mice expressing lower levels of Pgc-1α are exposed to HFD, they present AMD-like abnormalities in RPE and retinal morphology and function. These abnormalities include basal laminar deposits, thickening of Bruch's membrane with drusen marker-containing deposits, RPE and photoreceptor degeneration, decreased mitochondrial activity, increased levels of reactive oxygen species, decreased autophagy dynamics/flux, and increased inflammatory response in the RPE and retina. Our study shows that Pgc-1α is important in outer retina biology and that Pgc-1α+/− mice fed with HFD provide a promising model to study AMD, opening doors for novel treatment strategies.http://dmm.biologists.org/content/11/9/dmm032698RPEAMDRetinal degenerationPGC-1αHigh-fat dietMitochondriaAutophagy |
| spellingShingle | Meng Zhang Yi Chu Joseph Mowery Brandon Konkel Susana Galli Alexander C. Theos Nady Golestaneh Pgc-1α repression and high-fat diet induce age-related macular degeneration-like phenotypes in mice Disease Models & Mechanisms RPE AMD Retinal degeneration PGC-1α High-fat diet Mitochondria Autophagy |
| title | Pgc-1α repression and high-fat diet induce age-related macular degeneration-like phenotypes in mice |
| title_full | Pgc-1α repression and high-fat diet induce age-related macular degeneration-like phenotypes in mice |
| title_fullStr | Pgc-1α repression and high-fat diet induce age-related macular degeneration-like phenotypes in mice |
| title_full_unstemmed | Pgc-1α repression and high-fat diet induce age-related macular degeneration-like phenotypes in mice |
| title_short | Pgc-1α repression and high-fat diet induce age-related macular degeneration-like phenotypes in mice |
| title_sort | pgc 1α repression and high fat diet induce age related macular degeneration like phenotypes in mice |
| topic | RPE AMD Retinal degeneration PGC-1α High-fat diet Mitochondria Autophagy |
| url | http://dmm.biologists.org/content/11/9/dmm032698 |
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