Modulating sphingolipid biosynthetic pathway rescues photoreceptor degeneration
Modulating sphingolipid biosynthetic pathway rescues photoreceptor degeneration
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DOI：
10.1126/science.1080549
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发表时间：
2003-03-14
期刊：
影响因子：
56.9
通讯作者：
Acharya, JK
中科院分区：
文献类型：
--
作者：
Acharya, U;Patel, S;Acharya, JK
果蝇光转导级联系统是一种典型的鸟核苷酸结合蛋白偶联受体信号系统，它的蛋白质突变会导致视网膜退化，并已被用作理解人类退行性疾病的模型。在这里，调节鞘磷脂生物合成途径挽救了果蝇突变体的视网膜退化。果蝇中性神经酰胺酶的靶向表达挽救了arrestin和磷脂酶C突变体的视网膜变性。通过从头合成鞘脂生物合成途径的通量减少也抑制了这些突变体的退化。这两种遗传背景都调节了内吞机制，因为它们抑制了动力蛋白突变体中的缺陷。表达神经酰胺酶的arrestin突变果蝇的退变抑制与神经酰胺水平的降低有关。因此，鞘磷脂代谢酶可能是治疗视网膜变性的合适靶点。
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.