Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium

Jingyu Yao, Lin Jia, Naheed Khan, Chengmao Lin, Sayak K. Mitter, Michael E. Boulton, Joshua L. Dunaief, Daniel J. Klionsky, Jun Lin Guan, Debra A. Thompson, David N. Zacks

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Autophagy regulates cellular homeostasis and response to environmental stress. Within the retinal pigment epithelium (RPE) of the eye, the level of autophagy can change with both age and disease. The purpose of this study is to determine the relationship between reduced autophagy and age-related degeneration of the RPE. The gene encoding RB1CC1/FIP200 (RB1-inducible coiled-coil 1), a protein essential for induction of autophagy, was selectively knocked out in the RPE by crossing Best1-Cre mice with mice in which the Rb1cc1 gene was flanked with Lox-P sites (Rb1cc1flox/flox). Ex vivo and in vivo analyses, including western blot, immunohistochemistry, transmission electron microscopy, fundus photography, optical coherence tomography, fluorescein angiography, and electroretinography were performed to assess the structure and function of the retina as a function of age. Deletion of Rb1cc1 resulted in multiple autophagy defects within the RPE including decreased conversion of LC3-I to LC3-II, accumulation of autophagy-targeted precursors, and increased numbers of mitochondria. Age-dependent degeneration of the RPE occurred, with formation of atrophic patches, subretinal migration of activated microglial cells, subRPE deposition of inflammatory and oxidatively damaged proteins, subretinal drusenoid deposits, and occasional foci of choroidal neovascularization. There was secondary loss of photoreceptors overlying the degenerated RPE and reduction in the electroretinogram. These observations are consistent with a critical role of autophagy in the maintenance of normal homeostasis in the aging RPE, and indicate that disruption of autophagy leads to retinal phenotypes associated with age-related degeneration.

Original languageEnglish (US)
Pages (from-to)939-953
Number of pages15
JournalAutophagy
Volume11
Issue number6
DOIs
StatePublished - Jan 1 2015

Fingerprint

Retinal Pigment Epithelium
Autophagy
Pigment Epithelium of Eye
Homeostasis
Electroretinography
Choroidal Neovascularization
Fluorescein Angiography
Photography
Optical Coherence Tomography
Transmission Electron Microscopy
Genes
Retina
Mitochondria
Proteins
Western Blotting
Immunohistochemistry
Maintenance
Phenotype

Keywords

  • Age-related macular degeneration
  • FIP200
  • Photoreceptor
  • Retina
  • Retinal pigment epithelium

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Yao, J., Jia, L., Khan, N., Lin, C., Mitter, S. K., Boulton, M. E., ... Zacks, D. N. (2015). Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium. Autophagy, 11(6), 939-953. https://doi.org/10.1080/15548627.2015.1041699

Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium. / Yao, Jingyu; Jia, Lin; Khan, Naheed; Lin, Chengmao; Mitter, Sayak K.; Boulton, Michael E.; Dunaief, Joshua L.; Klionsky, Daniel J.; Guan, Jun Lin; Thompson, Debra A.; Zacks, David N.

In: Autophagy, Vol. 11, No. 6, 01.01.2015, p. 939-953.

Research output: Contribution to journalArticle

Yao, J, Jia, L, Khan, N, Lin, C, Mitter, SK, Boulton, ME, Dunaief, JL, Klionsky, DJ, Guan, JL, Thompson, DA & Zacks, DN 2015, 'Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium', Autophagy, vol. 11, no. 6, pp. 939-953. https://doi.org/10.1080/15548627.2015.1041699
Yao, Jingyu ; Jia, Lin ; Khan, Naheed ; Lin, Chengmao ; Mitter, Sayak K. ; Boulton, Michael E. ; Dunaief, Joshua L. ; Klionsky, Daniel J. ; Guan, Jun Lin ; Thompson, Debra A. ; Zacks, David N. / Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium. In: Autophagy. 2015 ; Vol. 11, No. 6. pp. 939-953.
@article{f51beb947e4448d18df7beec41ab0b2a,
title = "Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium",
abstract = "Autophagy regulates cellular homeostasis and response to environmental stress. Within the retinal pigment epithelium (RPE) of the eye, the level of autophagy can change with both age and disease. The purpose of this study is to determine the relationship between reduced autophagy and age-related degeneration of the RPE. The gene encoding RB1CC1/FIP200 (RB1-inducible coiled-coil 1), a protein essential for induction of autophagy, was selectively knocked out in the RPE by crossing Best1-Cre mice with mice in which the Rb1cc1 gene was flanked with Lox-P sites (Rb1cc1flox/flox). Ex vivo and in vivo analyses, including western blot, immunohistochemistry, transmission electron microscopy, fundus photography, optical coherence tomography, fluorescein angiography, and electroretinography were performed to assess the structure and function of the retina as a function of age. Deletion of Rb1cc1 resulted in multiple autophagy defects within the RPE including decreased conversion of LC3-I to LC3-II, accumulation of autophagy-targeted precursors, and increased numbers of mitochondria. Age-dependent degeneration of the RPE occurred, with formation of atrophic patches, subretinal migration of activated microglial cells, subRPE deposition of inflammatory and oxidatively damaged proteins, subretinal drusenoid deposits, and occasional foci of choroidal neovascularization. There was secondary loss of photoreceptors overlying the degenerated RPE and reduction in the electroretinogram. These observations are consistent with a critical role of autophagy in the maintenance of normal homeostasis in the aging RPE, and indicate that disruption of autophagy leads to retinal phenotypes associated with age-related degeneration.",
keywords = "Age-related macular degeneration, FIP200, Photoreceptor, Retina, Retinal pigment epithelium",
author = "Jingyu Yao and Lin Jia and Naheed Khan and Chengmao Lin and Mitter, {Sayak K.} and Boulton, {Michael E.} and Dunaief, {Joshua L.} and Klionsky, {Daniel J.} and Guan, {Jun Lin} and Thompson, {Debra A.} and Zacks, {David N.}",
year = "2015",
month = "1",
day = "1",
doi = "10.1080/15548627.2015.1041699",
language = "English (US)",
volume = "11",
pages = "939--953",
journal = "Autophagy",
issn = "1554-8627",
publisher = "Landes Bioscience",
number = "6",

}

TY - JOUR

T1 - Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium

AU - Yao, Jingyu

AU - Jia, Lin

AU - Khan, Naheed

AU - Lin, Chengmao

AU - Mitter, Sayak K.

AU - Boulton, Michael E.

AU - Dunaief, Joshua L.

AU - Klionsky, Daniel J.

AU - Guan, Jun Lin

AU - Thompson, Debra A.

AU - Zacks, David N.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Autophagy regulates cellular homeostasis and response to environmental stress. Within the retinal pigment epithelium (RPE) of the eye, the level of autophagy can change with both age and disease. The purpose of this study is to determine the relationship between reduced autophagy and age-related degeneration of the RPE. The gene encoding RB1CC1/FIP200 (RB1-inducible coiled-coil 1), a protein essential for induction of autophagy, was selectively knocked out in the RPE by crossing Best1-Cre mice with mice in which the Rb1cc1 gene was flanked with Lox-P sites (Rb1cc1flox/flox). Ex vivo and in vivo analyses, including western blot, immunohistochemistry, transmission electron microscopy, fundus photography, optical coherence tomography, fluorescein angiography, and electroretinography were performed to assess the structure and function of the retina as a function of age. Deletion of Rb1cc1 resulted in multiple autophagy defects within the RPE including decreased conversion of LC3-I to LC3-II, accumulation of autophagy-targeted precursors, and increased numbers of mitochondria. Age-dependent degeneration of the RPE occurred, with formation of atrophic patches, subretinal migration of activated microglial cells, subRPE deposition of inflammatory and oxidatively damaged proteins, subretinal drusenoid deposits, and occasional foci of choroidal neovascularization. There was secondary loss of photoreceptors overlying the degenerated RPE and reduction in the electroretinogram. These observations are consistent with a critical role of autophagy in the maintenance of normal homeostasis in the aging RPE, and indicate that disruption of autophagy leads to retinal phenotypes associated with age-related degeneration.

AB - Autophagy regulates cellular homeostasis and response to environmental stress. Within the retinal pigment epithelium (RPE) of the eye, the level of autophagy can change with both age and disease. The purpose of this study is to determine the relationship between reduced autophagy and age-related degeneration of the RPE. The gene encoding RB1CC1/FIP200 (RB1-inducible coiled-coil 1), a protein essential for induction of autophagy, was selectively knocked out in the RPE by crossing Best1-Cre mice with mice in which the Rb1cc1 gene was flanked with Lox-P sites (Rb1cc1flox/flox). Ex vivo and in vivo analyses, including western blot, immunohistochemistry, transmission electron microscopy, fundus photography, optical coherence tomography, fluorescein angiography, and electroretinography were performed to assess the structure and function of the retina as a function of age. Deletion of Rb1cc1 resulted in multiple autophagy defects within the RPE including decreased conversion of LC3-I to LC3-II, accumulation of autophagy-targeted precursors, and increased numbers of mitochondria. Age-dependent degeneration of the RPE occurred, with formation of atrophic patches, subretinal migration of activated microglial cells, subRPE deposition of inflammatory and oxidatively damaged proteins, subretinal drusenoid deposits, and occasional foci of choroidal neovascularization. There was secondary loss of photoreceptors overlying the degenerated RPE and reduction in the electroretinogram. These observations are consistent with a critical role of autophagy in the maintenance of normal homeostasis in the aging RPE, and indicate that disruption of autophagy leads to retinal phenotypes associated with age-related degeneration.

KW - Age-related macular degeneration

KW - FIP200

KW - Photoreceptor

KW - Retina

KW - Retinal pigment epithelium

UR - http://www.scopus.com/inward/record.url?scp=84940837701&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84940837701&partnerID=8YFLogxK

U2 - 10.1080/15548627.2015.1041699

DO - 10.1080/15548627.2015.1041699

M3 - Article

C2 - 26075877

AN - SCOPUS:84940837701

VL - 11

SP - 939

EP - 953

JO - Autophagy

JF - Autophagy

SN - 1554-8627

IS - 6

ER -