Cargando…

Cholesterol-mediated activation of acid sphingomyelinase disrupts autophagy in the retinal pigment epithelium

Autophagy is an essential mechanism for clearing damaged organelles and proteins within the cell. As with neurodegenerative diseases, dysfunctional autophagy could contribute to blinding diseases such as macular degeneration. However, precisely how inefficient autophagy promotes retinal damage is un...

Descripción completa

Detalles Bibliográficos
Autores principales: Toops, Kimberly A., Tan, Li Xuan, Jiang, Zhichun, Radu, Roxana A., Lakkaraju, Aparna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279221/
https://www.ncbi.nlm.nih.gov/pubmed/25378587
http://dx.doi.org/10.1091/mbc.E14-05-1028
_version_ 1782350643750502400
author Toops, Kimberly A.
Tan, Li Xuan
Jiang, Zhichun
Radu, Roxana A.
Lakkaraju, Aparna
author_facet Toops, Kimberly A.
Tan, Li Xuan
Jiang, Zhichun
Radu, Roxana A.
Lakkaraju, Aparna
author_sort Toops, Kimberly A.
collection PubMed
description Autophagy is an essential mechanism for clearing damaged organelles and proteins within the cell. As with neurodegenerative diseases, dysfunctional autophagy could contribute to blinding diseases such as macular degeneration. However, precisely how inefficient autophagy promotes retinal damage is unclear. In this study, we investigate innate mechanisms that modulate autophagy in the retinal pigment epithelium (RPE), a key site of insult in macular degeneration. High-speed live imaging of polarized adult primary RPE cells and data from a mouse model of early-onset macular degeneration identify a mechanism by which lipofuscin bisretinoids, visual cycle metabolites that progressively accumulate in the RPE, disrupt autophagy. We demonstrate that bisretinoids trap cholesterol and bis(monoacylglycero)phosphate, an acid sphingomyelinase (ASMase) cofactor, within the RPE. ASMase activation increases cellular ceramide, which promotes tubulin acetylation on stabilized microtubules. Live-imaging data show that autophagosome traffic and autophagic flux are inhibited in RPE with acetylated microtubules. Drugs that remove excess cholesterol or inhibit ASMase reverse this cascade of events and restore autophagosome motility and autophagic flux in the RPE. Because accumulation of lipofuscin bisretinoids and abnormal cholesterol homeostasis are implicated in macular degeneration, our studies suggest that ASMase could be a potential therapeutic target to ensure the efficient autophagy that maintains RPE health.
format Online
Article
Text
id pubmed-4279221
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher The American Society for Cell Biology
record_format MEDLINE/PubMed
spelling pubmed-42792212015-03-16 Cholesterol-mediated activation of acid sphingomyelinase disrupts autophagy in the retinal pigment epithelium Toops, Kimberly A. Tan, Li Xuan Jiang, Zhichun Radu, Roxana A. Lakkaraju, Aparna Mol Biol Cell Articles Autophagy is an essential mechanism for clearing damaged organelles and proteins within the cell. As with neurodegenerative diseases, dysfunctional autophagy could contribute to blinding diseases such as macular degeneration. However, precisely how inefficient autophagy promotes retinal damage is unclear. In this study, we investigate innate mechanisms that modulate autophagy in the retinal pigment epithelium (RPE), a key site of insult in macular degeneration. High-speed live imaging of polarized adult primary RPE cells and data from a mouse model of early-onset macular degeneration identify a mechanism by which lipofuscin bisretinoids, visual cycle metabolites that progressively accumulate in the RPE, disrupt autophagy. We demonstrate that bisretinoids trap cholesterol and bis(monoacylglycero)phosphate, an acid sphingomyelinase (ASMase) cofactor, within the RPE. ASMase activation increases cellular ceramide, which promotes tubulin acetylation on stabilized microtubules. Live-imaging data show that autophagosome traffic and autophagic flux are inhibited in RPE with acetylated microtubules. Drugs that remove excess cholesterol or inhibit ASMase reverse this cascade of events and restore autophagosome motility and autophagic flux in the RPE. Because accumulation of lipofuscin bisretinoids and abnormal cholesterol homeostasis are implicated in macular degeneration, our studies suggest that ASMase could be a potential therapeutic target to ensure the efficient autophagy that maintains RPE health. The American Society for Cell Biology 2015-01-01 /pmc/articles/PMC4279221/ /pubmed/25378587 http://dx.doi.org/10.1091/mbc.E14-05-1028 Text en © 2015 Toops et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Toops, Kimberly A.
Tan, Li Xuan
Jiang, Zhichun
Radu, Roxana A.
Lakkaraju, Aparna
Cholesterol-mediated activation of acid sphingomyelinase disrupts autophagy in the retinal pigment epithelium
title Cholesterol-mediated activation of acid sphingomyelinase disrupts autophagy in the retinal pigment epithelium
title_full Cholesterol-mediated activation of acid sphingomyelinase disrupts autophagy in the retinal pigment epithelium
title_fullStr Cholesterol-mediated activation of acid sphingomyelinase disrupts autophagy in the retinal pigment epithelium
title_full_unstemmed Cholesterol-mediated activation of acid sphingomyelinase disrupts autophagy in the retinal pigment epithelium
title_short Cholesterol-mediated activation of acid sphingomyelinase disrupts autophagy in the retinal pigment epithelium
title_sort cholesterol-mediated activation of acid sphingomyelinase disrupts autophagy in the retinal pigment epithelium
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279221/
https://www.ncbi.nlm.nih.gov/pubmed/25378587
http://dx.doi.org/10.1091/mbc.E14-05-1028
work_keys_str_mv AT toopskimberlya cholesterolmediatedactivationofacidsphingomyelinasedisruptsautophagyintheretinalpigmentepithelium
AT tanlixuan cholesterolmediatedactivationofacidsphingomyelinasedisruptsautophagyintheretinalpigmentepithelium
AT jiangzhichun cholesterolmediatedactivationofacidsphingomyelinasedisruptsautophagyintheretinalpigmentepithelium
AT raduroxanaa cholesterolmediatedactivationofacidsphingomyelinasedisruptsautophagyintheretinalpigmentepithelium
AT lakkarajuaparna cholesterolmediatedactivationofacidsphingomyelinasedisruptsautophagyintheretinalpigmentepithelium