Pgc-1α repression and high-fat diet induce age-related macular degeneration-like phenotypes in mice
| Autor: | Nady Golestaneh, Meng Zhang, Susana Galli, Brandon Konkel, Joseph Mowery, Yi Chu, Alexander C. Theos |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Retinal degeneration medicine.medical_specialty genetic structures Neuroscience (miscellaneous) lcsh:Medicine PGC-1α Medicine (miscellaneous) AMD Drusen Mitochondrion Biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Immunology and Microbiology (miscellaneous) Internal medicine lcsh:Pathology Autophagy medicine Retina Retinal pigment epithelium lcsh:R Retinal Macular degeneration medicine.disease eye diseases Mitochondria High-fat diet 030104 developmental biology medicine.anatomical_structure Endocrinology chemistry RPE sense organs PPARGC1A 030217 neurology & neurosurgery lcsh:RB1-214 Research Article |
| Zdroj: | Disease Models & Mechanisms Disease Models & Mechanisms, Vol 11, Iss 9 (2018) |
| ISSN: | 1754-8411 1754-8403 |
| Popis: | 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. Summary: A new mouse model has been established that exhibits characteristics of human age-related macular degeneration; the model will facilitate further studies of AMD disease mechanisms. |
| Databáze: | OpenAIRE |
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