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Modulating Sphingolipid Biosynthetic Pathway Rescues Photoreceptor Degeneration

Science, 14 March 2003
Vol. 299, Issue 5613, p. 1740-1743
DOI: 10.1126/science.1080549

Modulating Sphingolipid Biosynthetic Pathway Rescues Photoreceptor Degeneration

  1. Usha Acharya1,*,
  2. Shetal Patel1,
  3. Edmund Koundakjian2,
  4. Kunio Nagashima3,
  5. Xianlin Han4,
  6. Jairaj K. Acharya1,*
  1. 1 Regulation of Cell Growth Laboratory, National Cancer Institute–Frederick, Frederick, MD 21702, USA.
  2. 2 Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
  3. 3 Electron Microscopy Facility/Image Analysis Laboratory, Science Applications International Corporation, Frederick, MD 21702, USA.
  4. 4 Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.

Abstract

Mutations in proteins of the Drosophilaphototransduction 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 inDrosophila mutants. Targeted expression ofDrosophila 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.

  • * To whom correspondence should be addressed. E-mail: acharyaj{at}mail.ncifcrf.gov (J.K.A.), acharyau{at}mail.ncifcrf.gov (U.A.)

  • Received for publication 18 November 2002.
  • Accepted for publication 3 January 2003.

Citation:

U. Acharya, S. Patel, E. Koundakjian, K. Nagashima, X. Han, and J. K. Acharya, Modulating Sphingolipid Biosynthetic Pathway Rescues Photoreceptor Degeneration. Science 299, 1740-1743 (2003).

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