A Drosophila model of the Niemann-Pick type C lysosome storage disease:: dnpc1a is required for molting and sterol homeostasis
A Drosophila model of the Niemann-Pick type C lysosome storage disease:: dnpc1a is required for molting and sterol homeostasis
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DOI：
10.1242/dev.02079
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发表时间：
2005-11-01
期刊：
影响因子：
4.6
通讯作者：
Scott, MP
中科院分区：
文献类型：
--
作者：
Huang, X;Suyama, K;Scott, MP
C型尼曼-皮克病（NPC）是一种致死性常染色体隐性遗传神经退行性疾病，其特征是未酯化胆固醇在异常细胞器中的不适当积累。这种疾病是由于两个基因中的任何一个突变引起的，NPC 1编码与Hedgehog受体Patched相关的跨膜蛋白，NPC 2编码分泌的胆固醇结合蛋白。npc 1突变小鼠可以通过特定类固醇治疗部分获救。我们通过突变dnpc 1a建立了果蝇NPC模型，dnpc 1a是与哺乳动物NPCL细胞相关的两个果蝇基因之一，在dnpc 1a突变体的体内，细胞以点状模式积累甾醇，就像在NPC 1突变的个体中一样。这些突变体只发育到第一个幼虫阶段，无法蜕皮。正常的第一龄期后的蜕皮恢复到不同程度的喂养突变体的类固醇蜕皮激素20-羟基蜕皮激素，或蜕皮激素生物合成，胆固醇和7-脱氢胆固醇的前体。DNPC 1A通常在产生蜕皮激素的环腺中高度表达。在其他突变的果蝇中，dnpc 1a的环腺特异性表达允许发育到成年期，这表明突变体中蜕皮激素的缺乏是死亡的原因。我们提出dnpc 1a突变体中的甾醇被困在异常的细胞器中，导致内质网和/或环状腺细胞线粒体中甾醇不足，从而导致蜕皮激素合成不足。
Niemann-Pick type C (NPC) disease is a fatal autosomal-recessive neurodegenerative disorder characterized by the inappropriate accumulation of unesterified cholesterol in aberrant organelles. The disease is due to mutations in either of two genes, NPC1, which encodes a transmembrane protein related to the Hedgehog receptor Patched, and NPC2, which encodes a secreted cholesterol-binding protein. Npc1 mutant mice can be partially rescued by treatment with specific steroids. We have created a Drosophild NPC model by mutating dnpc1a, one of two Drosophild genes related to mammalian NPCL Cells throughout the bodies of dnpc1a mutants accumulated sterol in a punctate pattern, as in individuals with NPC1 mutations. The mutants developed only to the first larval stage and were unable to molt. Molting after the normal first instar period was restored to various degrees by feeding the mutants the steroid molting hormone 20-hydroxyecdysone, or the precursors of ecdysone biosynthesis, cholesterol and 7-dehydrocholesterol. dnpc1a is normally highly expressed in the ecdysone-producing ring gland. Ring gland-specific expression of dnpc1a in otherwise mutant flies allowed development to adulthood, suggesting that the lack of ecdysone in the mutants is the cause of death. We propose that dnpc1a mutants have sterols trapped in aberrant organelles, leading to a shortage of sterol in the endoplasmic reticulum and/or mitochondria of ring gland cells, and, consequently, inadequate ecdysone synthesis.