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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}mail.ncifcrf.gov (J.K.A.), acharyau{at}mail.ncifcrf.gov (U.A.)



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