title: Modulating sphingolipid biosynthetic pathway rescues photoreceptor degeneration.
abstract: 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.
authors.affiliation: Regulation of Cell Growth Laboratory, National Cancer Institute-Frederick, Frederick, MD 21702, USA. acharyau@mail.ncifcrf.gov
authors.forename: Usha
authors.initials: U
authors.lastname: Acharya
authors.forename: Shetal
authors.initials: S
authors.lastname: Patel
authors.forename: Edmund
authors.initials: E
authors.lastname: Koundakjian
authors.forename: Kunio
authors.initials: K
authors.lastname: Nagashima
authors.forename: Xianlin
authors.initials: X
authors.lastname: Han
authors.forename: Jairaj K
authors.initials: JK
authors.lastname: Acharya
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D019390:Arrestins / Q000235:genetics / Q000378:metabolism; D055572:Ceramidases; D002518:Ceramides / Q000096:biosynthesis / Q000378:metabolism*; D002966:Clathrin / Q000502:physiology; D003001:Cloning, Molecular; D003433:Crosses, Genetic; D004330:Drosophila / Q000235:genetics / Q000502:physiology*; D034281:Dynamins / Q000235:genetics / Q000502:physiology; D004596:Electroretinography; D004705:Endocytosis; D017344:Genes, Insect; D008027:Light; D009154:Mutation; D009336:Necrosis; D055576:Neutral Ceramidase; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017956:Photoreceptor Cells, Invertebrate / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D011956:Receptors, Cell Surface / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics; D012243:Rhodopsin / Q000378:metabolism; D051102:Serine C-Palmitoyltransferase; D021241:Spectrometry, Mass, Electrospray Ionization; D013110:Sphingosine / Q000378:metabolism; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism; D014785:Vision, Ocular
chemical_list: D019390:Arrestins; D002518:Ceramides; D002966:Clathrin; D010750:Phosphoproteins; D011956:Receptors, Cell Surface; D012243:Rhodopsin; D000217:Acyltransferases; D051102:Serine C-Palmitoyltransferase; D010738:Type C Phospholipases; D000581:Amidohydrolases; C526744:ASAH2 protein, human; D055572:Ceramidases; D055576:Neutral Ceramidase; D034281:Dynamins; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D013110:Sphingosine