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

• Main 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
• Format: Article
• Language: English
• Published: Elsevier 2016-05-01
• Series: Journal of Lipid Research
• Subjects: retina; P23H line 1 rats; photoreceptors; apoptosis; ceramide; hexosyl-ceramide
• Online Access: http://www.sciencedirect.com/science/article/pii/S0022227520309858

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.