Niemann Pick C disease in Drosophila

果蝇尼曼皮克 C 病

• 批准号: 6700857
• 负责人: KRISHNA MOORTHI BHAT
• 金额: $ 25.27万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6700857
• 关键词: Drosophilidae; Niemann Pick disease; arthropod genetics; cholesterol; developmental genetics; gene mutation; inclusion body; mutant; neurogenesis; neurons; tumor suppressor genes; tumor suppressor proteins

DESCRIPTION (provided by applicant): Niemann-Pick type C (NPC) is an inherited, pediatric neurodegenerative disease thought to be due to the accumulation of unesterified cholesterol in neurons. In the model organism Drosophila, there are two NPCI genes, NPC1a and NPC1b. However, there are no known point mutations in these genes, and consequently, their role in disease or development is not known. The NPC1 proteins have significant homology to the developmental regulator and tumor suppressor morphogen Patched (Ptc).The first hypothesis driving this proposal is that ptc mutant files develop a NPC-like disease. This is based on our following findings: (1) we have isolated an adult specific allele of ptc and these flies show progressive, age-dependent locomotor deficits, (2) the brains from these mutants show neurons with inclusion bodies similar to the inclusions found in neurons of NPC and several other lysosomal storage disorders. The second hypothesis driving this proposal is that the primary cause for the NPC disease-state in ptc flies is not the accumulation of cholesterol in neurons. This is based on our finding that overloading the cholesterol pathway in wild type leads to accumulation of cholesterol and formation of inclusion bodies in neurons; however, these flies do not develop any of the behavioral defects. Similarly, feeding cholesterol to mutant flies does not worsen the disease-state. These are consistent with the previous observation that there is no correlation between the extent of presence of inclusions and the severity of the disease. The third hypothesis driving this proposal is that the NPC1 proteins in Drosophila might regulate developmental processes in conjunction with Ptc. This is based on our observation that some of the developmental defects in ptc mutants are partially penetrant and that the two NPC1 genes are the closest of ptc in flies and might complement the loss of Ptc activity.Thus, our specific aims are: 1) Determine why ptc mutant flies develop the NPC-like disease: the molecular basis, 2) Isolate dNPC1 mutations and determine: a) if loss of function for these genes leads to the NPC disease, b) if the two genes are required for neurogenesis, and c) the relationship between Ptc and NPC1 in disease and development, 3) Perform modifier screens to isolate adult specific mutations in dNPC1 genes. This work will provide insight into the role of these proteins in neurodegenerative diseases and development.

描述(申请人提供)：Niemann-Pick C型(NPC)是一种遗传性的儿科神经退行性疾病，被认为是由于未酯化胆固醇在神经元中积累所致。在模式生物果蝇中，存在NPC1a和NPC1b两个NPC1基因。然而，这些基因中没有已知的点突变，因此，它们在疾病或发育中的作用尚不清楚。NPC1蛋白与发育调节因子和肿瘤抑制因子形态原补丁(PTC)有显著的同源性。支持这一提议的第一个假设是PTC突变文件发展为鼻咽癌样病。这是基于我们的以下发现：(1)我们分离出了PTC的一个成人特有等位基因，这些果蝇表现出进行性的、年龄相关的运动障碍，(2)这些突变体的大脑显示出与鼻咽癌和其他几种溶酶体储存障碍的神经元中发现的包涵体类似的包涵体。支持这一建议的第二个假设是，PTC果蝇鼻咽癌疾病状态的主要原因不是神经元中胆固醇的积累。这是基于我们的发现，在野生型中，过载的胆固醇途径会导致胆固醇在神经元中积累并形成包涵体；然而，这些果蝇不会发展出任何行为缺陷。同样，给突变果蝇喂食胆固醇并不会恶化疾病状态。这与之前的观察一致，即包裹体的存在程度与疾病的严重程度之间没有相关性。支持这一提议的第三个假设是，果蝇中的NPC1蛋白可能与PTC一起调节发育过程。这是基于我们观察到PTC突变体中的一些发育缺陷是部分穿透性的，并且这两个NPC1基因是果蝇中最接近的PTC基因，并且可能补充PTC活性的丧失。因此，我们的具体目标是：1)确定PTC突变果蝇发生鼻咽癌样疾病的分子基础，2)分离dNPC1突变，并确定：a)这些基因的功能丧失是否导致鼻咽癌疾病，b)这两个基因是否是神经发生所必需的，以及c)PTC和NPC1在疾病和发育中的关系，3)进行修饰性筛选以分离成人特有的dNPC1基因突变。这项工作将深入了解这些蛋白质在神经退行性疾病和发育中的作用。