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 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.
Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, McPherson Eye Research Institute, and.
Kimberly A
KA
Toops
Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53706.
Li Xuan
LX
Tan
Jules Stein Eye Institute, University of California, Los Angeles, Los Angeles, CA 90024.
Zhichun
Z
Jiang
Jules Stein Eye Institute, University of California, Los Angeles, Los Angeles, CA 90024.
Roxana A
RA
Radu
Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, McPherson Eye Research Institute, and Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53706 lakkaraju@wisc.edu.
Aparna
A
Lakkaraju
D000818:Animals; D001343:Autophagy; D002518:Ceramides / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D008062:Lipofuscin / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D008268:Macular Degeneration / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism; D050178:Monoglycerides / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism*; D055213:Retinal Pigment Epithelium / Q000648:ultrastructure*; D012176:Retinoids / Q000494:pharmacology; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism
C112040:A2-E (N-retinylidene-N-retinylethanolamine); D002518:Ceramides; D008062:Lipofuscin; D008246:Lysophospholipids; D050178:Monoglycerides; D012176:Retinoids; D014404:Tubulin; C012786:bis(monoacylglyceryl)phosphate; D002784:Cholesterol; D013108:Sphingomyelin Phosphodiesterase