PGC-1a repression and high fat diet induce age-related macular degeneration-like phenotypes in mice

Authors: ZHANG, MENG - Georgetown University Medical Center; CHU, YI - Georgetown University Medical Center; Mowery, Joseph; KONKEL, BRANDON - Georgetown University Medical Center; KONKEL, BRANDON - Georgetown University Medical Center; GALLI, SUSANA - Georgetown University Medical Center; THEOS, ALEXANDER - Georgetown University; GOLESTANEH, NADY - Georgetown University Medical Center

Submitted to: Disease Models and Mechanisms
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/13/2018
Publication Date: 6/20/2018
Citation: Zhang, M., Chu, Y., Mowery, J.D., Konkel, B., Konkel, B., Galli, S., Theos, A., Golestaneh, N. 2018. PGC-1a repression and high fat diet induce age-related macular degeneration-like phenotypes in mice. Disease Models and Mechanisms. https://doi.org/10.1242/dmm.032698.
DOI: https://doi.org/10.1242/dmm.032698

Interpretive Summary: Age-related macular degeneration is the major cause of blindness in the elderly in developed countries, and its prevalence is increasing with the aging population. Currently, there is no disease-altering treatment for the dry form of age-related macular degeneration. Age-related macular degeneration initially affects the retinal pigment epithelium in the eye, and gradually leads to secondary photoreceptor degeneration. We observed cellular organelle damage, autophagy dysfunction, and repression of a particular protein (PGC-1a) in retinal pigment epithelium tissue from age-related macular degeneration donor eyes. Further investigations on the effect of the PGC-1a protein repression was established through the development of a new mouse model by raising mice with and without PGC-1a gene and feeding the mice with a high fat diet. Mice expressing lower levels of the PGC-1a gene and exposed to high fat diet had age-related macular degeneration like abnormalities in the retinal pigment epithelium. These results open doors for novel drug treatment or nutritional prevention strategies for age-related macular degeneration by ophthalmologists, medical doctors, and nutritionists at hospitals, research institutions, and private practices.

Technical Abstract: 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 to AMD, and we have observed mitochondrial and autophagy dysfunction and repressed peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1a) in native RPE from AMD donor eyes and their respective induced pluripotent stem cell-derived RPE (AMD RPE-iPSC-RPE). To further investigate the effect of PGC-1a repression we have established a mouse model by feeding the PGC-1a +/- mice with high fat diet (HFD) and investigated the RPE and retinal health. Here we show that mice expressing lower levels of PGC-1a when exposed to HFD, present AMD-like abnormalities in RPE and retinal morphology and function. Our results show that the PGC-1a+/- mouse fed with HFD is a promising model to study AMD and opens doors for novel treatment strategies in AMD.