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Sphingolipid profile alters in retinal dystrophic P23H-1 rats and systemic FTY720 can delay retinal degeneration

Year: 2016
Type: article
Abstract: Retinal degeneration (RD) affects millions of people and is a major cause of ocular impairment and blindness. With a wide range of mutations and conditions leading to degeneration, targeting downstream processes is necessary for developing effective treatments. Ceramide and sphingosine-1-phosphate, a pair of bioactive sphingolipids, are involved in apoptosis and its prevention, respectively. Apoptotic cell death is a potential driver of RD, and in order to understand the mechanism of degeneration and potential treatments, we studied rhodopsin mutant RD model, P23H-1 rats. Investigating this genetic model of human RD allows us to investigate the association of sphingolipid metabolites with the degeneration of the retina in P23H-1 rats and the effects of a specific modulator of sphingolipid metabolism, FTY720. We found that P23H-1 rat retinas had altered sphingolipid profiles that, when treated with FTY720, were rebalanced closer to normal levels. FTY720-treated rats also showed protection from RD compared with their vehicle-treated littermates. Based on these data, we conclude that sphingolipid dysregulation plays a secondary role in retinal cell death, which may be common to many forms of RDs, and that the U.S. Food and Drug Administration-approved drug FTY720 or related compounds that modulate sphingolipid metabolism could potentially delay the cell death.
DOI: 10.1194/jlr.m063719
Authors: Megan Stiles, Hui Qi, Eleanor Sun, Jeremy Tan, Hunter Porter, Jeremy Allegood, Charles E. Chalfant, Douglas Yasumura, Michael T. Matthes, Matthew M. LaVail, Nawajes A. Mandal
Institutions: Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Virginia Commonwealth University, Hunter Holmes McGuire VA Medical Center, VCU Massey Comprehensive Cancer Center, University of California, San Francisco, University of California San Francisco Medical Center
Language: English
Open Access status: hybrid
Estimated APC paid: $3,430
Funders: U.S. Department of Veterans Affairs, National Institutes of Health, National Heart, Lung, and Blood Institute, National Eye Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Center for Research Resources
Awards: Sphingolipid Metabolism and Signaling in the Retina, Sphingolipid signaling in corneal wound healing and fibrosis, P30 - Core Grant for Vision Research, The role of the C1P/cPLA2alpha interaction in anaphylaxis, AB SCIEX 5500 QTRAP Mass Spectrometer for Lipidomics and Metabolomics Research, Mentoring Vision Research In Oklahoma, Cellular Mechanisms of Inherited Retinal Degeneration, The functional role of the cPLA2alpha/C1P interaction in sepsis resolution, NEUROPHYSIOLOGY OF INTERMEDIATE LEVEL VISION, G8173979607, Models of Retinal Degeneration, P30 Center Core Grant for Vision Research, Massey Cancer Center - Cancer Center Support Grant
OpenAlex ID: W2290864182
FWCI: 2.252
Cites: 73
Cited by: 42
Related to: 10