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 Mandal

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 vehicletreated 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.- Stiles, M., H. Qi, E. Sun, J. Tan, H. Porter, J. Allegood, C. E. Chalfant, D. Yasumura, M. T. Matthes, M. M. LaVail, and N. A. Mandal. Sphingolipid profile alters in retinal dystrophic P23H-1 rats and systemic FTY720 can delay retinal degeneration. J. Lipid Res. 2016. 57: 818-831.

Original languageEnglish (US)
Pages (from-to)818-831
Number of pages14
JournalJournal of lipid research
Volume57
Issue number5
DOIs
StatePublished - May 1 2016

Fingerprint

Retinal Degeneration
Sphingolipids
Rats
Cell death
Cell Death
Metabolism
Retina
Qi
Rhodopsin
Ceramides
Genetic Models
Solar System
United States Food and Drug Administration
Blindness
Metabolites
Fingolimod Hydrochloride
Sun
Modulators
Apoptosis
Lipids

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Endocrinology
  • Cell Biology

Cite this

Sphingolipid profile alters in retinal dystrophic P23H-1 rats and systemic FTY720 can delay retinal degeneration. / Stiles, Megan; Qi, Hui; Sun, Eleanor; Tan, Jeremy; Porter, Hunter; Allegood, Jeremy; Chalfant, Charles E.; Yasumura, Douglas; Matthes, Michael T.; Lavail, Matthew M.; Mandal, Nawajes.

In: Journal of lipid research, Vol. 57, No. 5, 01.05.2016, p. 818-831.

Research output: Contribution to journalArticle

Stiles, M, Qi, H, Sun, E, Tan, J, Porter, H, Allegood, J, Chalfant, CE, Yasumura, D, Matthes, MT, Lavail, MM & Mandal, N 2016, 'Sphingolipid profile alters in retinal dystrophic P23H-1 rats and systemic FTY720 can delay retinal degeneration', Journal of lipid research, vol. 57, no. 5, pp. 818-831. https://doi.org/10.1194/jlr.M063719
Stiles, Megan ; Qi, Hui ; Sun, Eleanor ; Tan, Jeremy ; Porter, Hunter ; Allegood, Jeremy ; Chalfant, Charles E. ; Yasumura, Douglas ; Matthes, Michael T. ; Lavail, Matthew M. ; Mandal, Nawajes. / Sphingolipid profile alters in retinal dystrophic P23H-1 rats and systemic FTY720 can delay retinal degeneration. In: Journal of lipid research. 2016 ; Vol. 57, No. 5. pp. 818-831.
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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 vehicletreated 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.- Stiles, M., H. Qi, E. Sun, J. Tan, H. Porter, J. Allegood, C. E. Chalfant, D. Yasumura, M. T. Matthes, M. M. LaVail, and N. A. Mandal. Sphingolipid profile alters in retinal dystrophic P23H-1 rats and systemic FTY720 can delay retinal degeneration. J. Lipid Res. 2016. 57: 818-831.",
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