title: Improved cell metabolism prolongs photoreceptor survival upon retinal-pigmented epithelium loss in the sodium iodate induced model of geographic atrophy.
abstract: Age-related macular degeneration (AMD) is characterized by malfunction and loss of retinal-pigmented epithelium (RPE) cells. Because the RPE transfers nutrients from the choriocapillaris to photoreceptor (PR), PRs are affected as well. Geographic atrophy (GA) is an advanced form of AMD characterized by severe vision impairment due to RPE loss over large areas. Currently there is no treatment to delay the degeneration of nutrient deprived PRs once RPE cells die. Here we show that cell-autonomous activation of the key regulator of cell metabolism, the kinase mammalian target of rapamycin complex 1 (mTORC1), delays PR death in the sodium iodate induced model of RPE atrophy. Consistent with this finding loss of mTORC1 in cones accelerates cone death as cones fail to balance demand with supply. Interestingly, promoting rod survival does not promote cone survival in this model of RPE atrophy as both, rods and cones suffer from a sick and dying RPE. The findings suggest that activation of metabolic genes downstream of mTORC1 can serve as a strategy to prolong PR survival when RPE cells malfunction or die.
authors.affiliation: Department of Ophthalmology and Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Zieger
authors.affiliation: Department of Ophthalmology and Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Punzo
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004596:Electroretinography; D004789:Enzyme Activation; D057092:Geographic Atrophy / Q000139:chemically induced / Q000473:pathology*; D007328:Insulin / Q000378:metabolism; D007452:Iodates; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000473:pathology*; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics
chemical_list: D007328:Insulin; D007452:Iodates; D046912:Multiprotein Complexes; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; C032285:sodium iodate
keywords: AMD; Gerotarget; cone degeneration; geographic atrophy; mTORC1; rod degeneration