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

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

doi:10.1194/jlr.m063719

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.

Highlights

Retinal degeneration (RD) affects millions of people and is a major cause of ocular impairment and blindness
We found no changes in the expression of major Cer degrading enzyme Asah1 in P23H line 1 (P23H-1) rats, but the expression of sphingosine kinase (Sphk) were significantly upregulated in P23H-1 retinas, which were reduced by FTY720 treatment (Fig. 6D; P < 0.05)
The processes of apoptotic cell death is integral to major retinal diseases including retinitis pigmentosa (RP), Stargardt’s disease, Leber’s congenital amaurosis, and age-related macular degeneration (AMD) [38,39,40,41]

Summary

Introduction

Retinal degeneration (RD) affects millions of people and is a major cause of ocular impairment and blindness. We conclude that P23H-1 retina accumulates Cer and its metabolic products significantly at early stages before major degeneration occurs (P22), and systemic treatment of FTY720 could downregulate the metabolic products of Cer. In P45 SD rats, long-term treatment of FTY720 seems to have reduced the level of total Hex-Cer, SM, and S1P in (Fig. 3B–D; * P < 0.01).

Results

Conclusion