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Dysfunctional autophagy in RPE, a contributing factor in age-related macular degeneration
Age-related macular degeneration (AMD) is a devastating neurodegenerative disease and a major cause of blindness in the developed world. Owing to its complexity and the lack of an adequate human model that recapitulates key aspects of the disease, the molecular mechanisms of AMD pathogenesis remain...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386365/ https://www.ncbi.nlm.nih.gov/pubmed/28055007 http://dx.doi.org/10.1038/cddis.2016.453 |
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author | Golestaneh, Nady Chu, Yi Xiao, Yang-Yu Stoleru, Gianna L Theos, Alexander C |
author_facet | Golestaneh, Nady Chu, Yi Xiao, Yang-Yu Stoleru, Gianna L Theos, Alexander C |
author_sort | Golestaneh, Nady |
collection | PubMed |
description | Age-related macular degeneration (AMD) is a devastating neurodegenerative disease and a major cause of blindness in the developed world. Owing to its complexity and the lack of an adequate human model that recapitulates key aspects of the disease, the molecular mechanisms of AMD pathogenesis remain poorly understood. Here we show that cultured human retinal pigment epithelium (RPE) from AMD donors (AMD RPE) are functionally impaired and exhibit distinct phenotypes compared with RPE cultured from normal donors (normal RPE). Accumulation of lipid droplets and glycogen granules, disintegration of mitochondria, and an increase in autophagosomes were observed in AMD RPE cultures. Compared with normal RPE, AMD RPE exhibit increased susceptibility to oxidative stress, produce higher levels of reactive oxygen species (ROS) under stress conditions, and showed reduced mitochondrial activity. Measurement of the ratio of LC3-II/ LC3-I, revealed impaired autophagy in AMD RPE as compared with normal RPE. Autophagic flux was also reduced in AMD RPE as compared with normal RPE, as shown by inability of AMD RPE to downregulate p62 levels during starvation. Impaired autophagic pathways were further shown by analyzing late autophagic vesicles; immunostaining with lysosome-associated membrane protein 1 (LAMP-1) antibody revealed enlarged and annular LAMP-1-positive organelles in AMD RPE as opposed to smaller discrete puncta observed in normal RPE. Our study provides insights into AMD cellular and molecular mechanisms, proposes dysfunctional autophagy as an underlying mechanism contributing to the pathophysiology of the disease, and opens up new avenues for development of novel treatment strategies. |
format | Online Article Text |
id | pubmed-5386365 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-53863652017-04-26 Dysfunctional autophagy in RPE, a contributing factor in age-related macular degeneration Golestaneh, Nady Chu, Yi Xiao, Yang-Yu Stoleru, Gianna L Theos, Alexander C Cell Death Dis Original Article Age-related macular degeneration (AMD) is a devastating neurodegenerative disease and a major cause of blindness in the developed world. Owing to its complexity and the lack of an adequate human model that recapitulates key aspects of the disease, the molecular mechanisms of AMD pathogenesis remain poorly understood. Here we show that cultured human retinal pigment epithelium (RPE) from AMD donors (AMD RPE) are functionally impaired and exhibit distinct phenotypes compared with RPE cultured from normal donors (normal RPE). Accumulation of lipid droplets and glycogen granules, disintegration of mitochondria, and an increase in autophagosomes were observed in AMD RPE cultures. Compared with normal RPE, AMD RPE exhibit increased susceptibility to oxidative stress, produce higher levels of reactive oxygen species (ROS) under stress conditions, and showed reduced mitochondrial activity. Measurement of the ratio of LC3-II/ LC3-I, revealed impaired autophagy in AMD RPE as compared with normal RPE. Autophagic flux was also reduced in AMD RPE as compared with normal RPE, as shown by inability of AMD RPE to downregulate p62 levels during starvation. Impaired autophagic pathways were further shown by analyzing late autophagic vesicles; immunostaining with lysosome-associated membrane protein 1 (LAMP-1) antibody revealed enlarged and annular LAMP-1-positive organelles in AMD RPE as opposed to smaller discrete puncta observed in normal RPE. Our study provides insights into AMD cellular and molecular mechanisms, proposes dysfunctional autophagy as an underlying mechanism contributing to the pathophysiology of the disease, and opens up new avenues for development of novel treatment strategies. Nature Publishing Group 2017-01 2017-01-05 /pmc/articles/PMC5386365/ /pubmed/28055007 http://dx.doi.org/10.1038/cddis.2016.453 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Original Article Golestaneh, Nady Chu, Yi Xiao, Yang-Yu Stoleru, Gianna L Theos, Alexander C Dysfunctional autophagy in RPE, a contributing factor in age-related macular degeneration |
title | Dysfunctional autophagy in RPE, a contributing factor in age-related macular degeneration |
title_full | Dysfunctional autophagy in RPE, a contributing factor in age-related macular degeneration |
title_fullStr | Dysfunctional autophagy in RPE, a contributing factor in age-related macular degeneration |
title_full_unstemmed | Dysfunctional autophagy in RPE, a contributing factor in age-related macular degeneration |
title_short | Dysfunctional autophagy in RPE, a contributing factor in age-related macular degeneration |
title_sort | dysfunctional autophagy in rpe, a contributing factor in age-related macular degeneration |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386365/ https://www.ncbi.nlm.nih.gov/pubmed/28055007 http://dx.doi.org/10.1038/cddis.2016.453 |
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