title: Two-Step Reactivation of Dormant Cones in Retinitis Pigmentosa.
abstract: Most retinitis pigmentosa (RP) mutations arise in rod photoreceptor genes, leading to diminished peripheral and nighttime vision. Using a pig model of autosomal-dominant RP, we show glucose becomes sequestered in the retinal pigment epithelium (RPE) and, thus, is not transported to photoreceptors. The resulting starvation for glucose metabolites impairs synthesis of cone visual pigment-rich outer segments (OSs), and then their mitochondrial-rich inner segments dissociate. Loss of these functional structures diminishes cone-dependent high-resolution central vision, which is utilized for most daily tasks. By transplanting wild-type rods, to restore glucose transport, or directly replacing glucose in the subretinal space, to bypass its retention in the RPE, we can regenerate cone functional structures, reactivating the dormant cells. Beyond providing metabolic building blocks for cone functional structures, we show glucose induces thioredoxin-interacting protein (Txnip) to regulate Akt signaling, thereby shunting metabolites toward aerobic glucose metabolism and regenerating cone OS synthesis.
authors.affiliation: Department of Ophthalmology & Visual Sciences, University of Louisville Health Sciences Center, Louisville, KY 40202, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology & Visual Sciences, University of Louisville Health Sciences Center, Louisville, KY 40202, USA; Department of Ophthalmology, College of Medicine, Kosin University, Busan, South Korea.
authors.forename: Sang Joon
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Ophthalmology & Visual Sciences, University of Louisville Health Sciences Center, Louisville, KY 40202, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Scott
authors.affiliation: Department of Ophthalmology & Visual Sciences, University of Louisville Health Sciences Center, Louisville, KY 40202, USA.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Ophthalmology & Visual Sciences, University of Louisville Health Sciences Center, Louisville, KY 40202, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Emery
authors.affiliation: Department of Ophthalmology & Visual Sciences, University of Louisville Health Sciences Center, Louisville, KY 40202, USA; Birth Defects Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA.
authors.forename: Yongqin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ezashi
authors.affiliation: Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Roberts
authors.affiliation: Department of Animal Sciences, Iowa State University, Ames, IA 50011, USA.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Ross
authors.affiliation: Department of Ophthalmology & Visual Sciences, University of Louisville Health Sciences Center, Louisville, KY 40202, USA.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Kaplan
authors.affiliation: Department of Ophthalmology & Visual Sciences, University of Louisville Health Sciences Center, Louisville, KY 40202, USA; Molecular Targets Program, James Graham Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA; Birth Defects Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA. Electronic address: douglas.dean@louisville.edu.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Dean
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000096:biosynthesis; D005947:Glucose / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000187:drug effects / Q000473:pathology* / Q000637:transplantation; D055211:Retinal Photoreceptor Cell Inner Segment / Q000187:drug effects / Q000378:metabolism; D055214:Retinal Photoreceptor Cell Outer Segment / Q000187:drug effects / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism; D017948:Retinal Rod Photoreceptor Cells / Q000187:drug effects / Q000473:pathology / Q000637:transplantation; D012174:Retinitis Pigmentosa / Q000473:pathology* / Q000503:physiopathology; D012243:Rhodopsin / Q000378:metabolism; D034421:Sus scrofa; D013879:Thioredoxins / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D035683:MicroRNAs; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D013879:Thioredoxins; D012243:Rhodopsin; D005947:Glucose