Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 299 (5613): 1740-1743

Copyright © 2003 by the American Association for the Advancement of Science

Modulating Sphingolipid Biosynthetic Pathway Rescues Photoreceptor Degeneration

Usha Acharya,1* Shetal Patel,1 Edmund Koundakjian,2 Kunio Nagashima,3 Xianlin Han,4 Jairaj K. Acharya1*

Mutations in proteins of the Drosophila phototransduction cascade, a prototypic guanine nucleotide-binding protein-coupled receptor signaling system, lead to retinal degeneration and have been used as models to understand human degenerative disorders. Here, modulating the sphingolipid biosynthetic pathway rescued retinal degeneration in Drosophila mutants. Targeted expression of Drosophila neutral ceramidase rescued retinal degeneration in arrestin and phospholipase C mutants. Decreasing flux through the de novo sphingolipid biosynthetic pathway also suppressed degeneration in these mutants. Both genetic backgrounds modulated the endocytic machinery because they suppressed defects in a dynamin mutant. Suppression of degeneration in arrestin mutant flies expressing ceramidase correlated with a decrease in ceramide levels. Thus, enzymes of sphingolipid metabolism may be suitable targets in the therapeutic management of retinal degeneration.

1 Regulation of Cell Growth Laboratory, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
2 Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
3 Electron Microscopy Facility/Image Analysis Laboratory, Science Applications International Corporation, Frederick, MD 21702, USA.
4 Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
*   To whom correspondence should be addressed. E-mail: acharyaj{at} (J.K.A.), acharyau{at} (U.A.)

Glucosylceramide Transferase Activity Is Critical for Encystation and Viable Cyst Production by an Intestinal Protozoan, Giardia lamblia.
T. L. Mendez, A. De Chatterjee, T. T. Duarte, F. Gazos-Lopes, L. Robles-Martinez, D. Roy, J. Sun, R. A. Maldonado, S. Roychowdhury, I. C. Almeida, et al. (2013)
J. Biol. Chem. 288, 16747-16760
   Abstract »    Full Text »    PDF »
Inhibition of de novo ceramide biosynthesis by FTY720 protects rat retina from light-induced degeneration.
H. Chen, J.-T. A. Tran, A. Eckerd, T.-P. Huynh, M. H. Elliott, R. S. Brush, and N. A. Mandal (2013)
J. Lipid Res. 54, 1616-1629
   Abstract »    Full Text »    PDF »
Ceramide Kinase-Like (CERKL) Interacts with Neuronal Calcium Sensor Proteins in the Retina in a Cation-Dependent Manner.
M. J. Nevet, S. Vekslin, A. M. Dizhoor, E. V. Olshevskaya, R. Tidhar, A. H. Futerman, and T. Ben-Yosef (2012)
Invest. Ophthalmol. Vis. Sci. 53, 4565-4574
   Abstract »    Full Text »    PDF »
Sphingosine kinases and their metabolites modulate endolysosomal trafficking in photoreceptors.
I. Yonamine, T. Bamba, N. K. Nirala, N. Jesmin, T. Kosakowska-Cholody, K. Nagashima, E. Fukusaki, J. K. Acharya, and U. Acharya (2011)
J. Cell Biol. 192, 557-567
   Abstract »    Full Text »    PDF »
CDase is a pan-ceramidase in Drosophila.
C. Yuan, R. P. Rao, N. Jesmin, T. Bamba, K. Nagashima, A. Pascual, T. Preat, E. Fukusaki, U. Acharya, and J. K. Acharya (2011)
Mol. Biol. Cell 22, 33-43
   Abstract »    Full Text »    PDF »
Inhibition of ceramide biosynthesis preserves photoreceptor structure and function in a mouse model of retinitis pigmentosa.
E. Strettoi, C. Gargini, E. Novelli, G. Sala, I. Piano, P. Gasco, and R. Ghidoni (2010)
PNAS 107, 18706-18711
   Abstract »    Full Text »    PDF »
Retinal Sphingolipids and Their Very-Long-Chain Fatty Acid-Containing Species.
R. S. Brush, J.-T. A. Tran, K. R. Henry, M. E. McClellan, M. H. Elliott, and M. N. A. Mandal (2010)
Invest. Ophthalmol. Vis. Sci. 51, 4422-4431
   Abstract »    Full Text »    PDF »
Regulating survival and development in the retina: key roles for simple sphingolipids.
N. P. Rotstein, G. E. Miranda, C. E. Abrahan, and O. L. German (2010)
J. Lipid Res. 51, 1247-1262
   Abstract »    Full Text »    PDF »
Synthesis of Sphingosine Is Essential for Oxidative Stress-Induced Apoptosis of Photoreceptors.
C. E. Abrahan, G. E. Miranda, D. L. Agnolazza, L. E. Politi, and N. P. Rotstein (2010)
Invest. Ophthalmol. Vis. Sci. 51, 1171-1180
   Abstract »    Full Text »    PDF »
Ceramide kinase regulates phospholipase C and phosphatidylinositol 4, 5, bisphosphate in phototransduction.
U. Dasgupta, T. Bamba, S. Chiantia, P. Karim, A. N. A. Tayoun, I. Yonamine, S. S. Rawat, R. P. Rao, K. Nagashima, E. Fukusaki, et al. (2009)
PNAS 106, 20063-20068
   Abstract »    Full Text »    PDF »
Overexpressing Temperature-Sensitive Dynamin Decelerates Phototransduction and Bundles Microtubules in Drosophila Photoreceptors.
P. T. Gonzalez-Bellido, T. J. Wardill, R. Kostyleva, I. A. Meinertzhagen, and M. Juusola (2009)
J. Neurosci. 29, 14199-14210
   Abstract »    Full Text »    PDF »
Mechanistic Insights into the Hydrolysis and Synthesis of Ceramide by Neutral Ceramidase.
T. Inoue, N. Okino, Y. Kakuta, A. Hijikata, H. Okano, H. M. Goda, M. Tani, N. Sueyoshi, K. Kambayashi, H. Matsumura, et al. (2009)
J. Biol. Chem. 284, 9566-9577
   Abstract »    Full Text »    PDF »
Regulation of neutral sphingomyelinase-2 by GSH: a new insight to the role of oxidative stress in aging-associated inflammation.
K. Rutkute, R. H. Asmis, and M. N. Nikolova-Karakashian (2007)
J. Lipid Res. 48, 2443-2452
   Abstract »    Full Text »    PDF »
Ceramidase Enhances Phospholipase C-induced Hemolysis by Pseudomonas aeruginosa.
N. Okino and M. Ito (2007)
J. Biol. Chem. 282, 6021-6030
   Abstract »    Full Text »    PDF »
Large-scale purification and characterization of recombinant Pseudomonas ceramidase: regulation by calcium.
B. X. Wu, C. F. Snook, M. Tani, E. E. Bullesbach, and Y. A. Hannun (2007)
J. Lipid Res. 48, 600-608
   Abstract »    Full Text »    PDF »
Diabetes Alters Sphingolipid Metabolism in the Retina: A Potential Mechanism of Cell Death in Diabetic Retinopathy.
T. E. Fox, X. Han, S. Kelly, A. H. Merrill Jr., R. E. Martin, R. E. Anderson, T. W. Gardner, and M. Kester (2006)
Diabetes 55, 3573-3580
   Abstract »    Full Text »    PDF »
An essential role for endocytosis of rhodopsin through interaction of visual arrestin with the AP-2 adaptor.
N. R. Orem, L. Xia, and P. J. Dolph (2006)
J. Cell Sci. 119, 3141-3148
   Abstract »    Full Text »    PDF »
Drosophila melanogaster Scramblases modulate synaptic transmission..
U. Acharya, M. B. Edwards, R. A. Jorquera, H. Silva, K. Nagashima, P. Labarca, and J. K. Acharya (2006)
J. Cell Biol. 173, 69-82
   Abstract »    Full Text »    PDF »
Ceramide is a Mediator of Apoptosis in Retina Photoreceptors..
O. L. German, G. E. Miranda, C. E. Abrahan, and N. P. Rotstein (2006)
Invest. Ophthalmol. Vis. Sci. 47, 1658-1668
   Abstract »    Full Text »    PDF »
Involvement of Neutral Ceramidase in Ceramide Metabolism at the Plasma Membrane and in Extracellular Milieu.
M. Tani, Y. Igarashi, and M. Ito (2005)
J. Biol. Chem. 280, 36592-36600
   Abstract »    Full Text »    PDF »
Rhodopsin maturation defects induce photoreceptor death by apoptosis: a fly model for RhodopsinPro23His human retinitis pigmentosa.
A. Galy, M. J. Roux, J. A. Sahel, T. Leveillard, and A. Giangrande (2005)
Hum. Mol. Genet. 14, 2547-2557
   Abstract »    Full Text »    PDF »
Golgi Fragmentation Is Associated with Ceramide-induced Cellular Effects.
W. Hu, R. Xu, G. Zhang, J. Jin, Z. M. Szulc, J. Bielawski, Y. A. Hannun, L. M. Obeid, and C. Mao (2005)
Mol. Biol. Cell 16, 1555-1567
   Abstract »    Full Text »    PDF »
Lip1p: a novel subunit of acyl-CoA ceramide synthase.
B. Vallee and H. Riezman (2005)
EMBO J. 24, 730-741
   Abstract »    Full Text »    PDF »
Molecular Cloning and Functional Analysis of Zebrafish Neutral Ceramidase.
Y. Yoshimura, M. Tani, N. Okino, H. Iida, and M. Ito (2004)
J. Biol. Chem. 279, 44012-44022
   Abstract »    Full Text »    PDF »
Ceramidase Regulates Synaptic Vesicle Exocytosis and Trafficking.
J. Rohrbough, E. Rushton, L. Palanker, E. Woodruff, H. J. G. Matthies, U. Acharya, J. K. Acharya, and K. Broadie (2004)
J. Neurosci. 24, 7789-7803
   Abstract »    Full Text »    PDF »
A. Kohyama-Koganeya, T. Sasamura, E. Oshima, E. Suzuki, S. Nishihara, R. Ueda, and Y. Hirabayashi (2004)
J. Biol. Chem. 279, 35995-36002
   Abstract »    Full Text »    PDF »
Conserved Amino Acid Residues in the COOH-terminal Tail Are Indispensable for the Correct Folding and Localization and Enzyme Activity of Neutral Ceramidase.
M. Tani, N. Okino, N. Sueyoshi, and M. Ito (2004)
J. Biol. Chem. 279, 29351-29358
   Abstract »    Full Text »    PDF »
Alternative, Nonapoptotic Programmed Cell Death: MEDIATION BY ARRESTIN 2, ERK2, AND Nur77.
S. Castro-Obregon, R. V. Rao, G. del Rio, S. F. Chen, K. S. Poksay, S. Rabizadeh, S. Vesce, X.-k. Zhang, R. A. Swanson, and D. E. Bredesen (2004)
J. Biol. Chem. 279, 17543-17553
   Abstract »    Full Text »    PDF »
Characterization of the Drosophila Sphingosine Kinases and Requirement for Sk2 in Normal Reproductive Function.
D. R. Herr, H. Fyrst, M. B. Creason, V. H. Phan, J. D. Saba, and G. L. Harris (2004)
J. Biol. Chem. 279, 12685-12694
   Abstract »    Full Text »    PDF »
Ceramidase expression facilitates membrane turnover and endocytosis of rhodopsin in photoreceptors.
U. Acharya, M. B. Mowen, K. Nagashima, and J. K. Acharya (2004)
PNAS 101, 1922-1926
   Abstract »    Full Text »    PDF »
Ceramide, Stress, and a "LAG" in Aging.
L. M. Obeid and Y. A. Hannun (2003)
Sci. Aging Knowl. Environ. 2003, pe27-27
   Abstract »    Full Text »
CELL BIOLOGY: A Matter of Life or Death.
R. Ranganathan (2003)
Science 299, 1677-1679
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882