Modeling Neurodegeneration and Adrenoleukodystrophy in Drosophila

果蝇神经变性和肾上腺脑白质营养不良建模

基本信息

批准号：
7643019
负责人：
Anthea Letsou
金额：
$ 37.58万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-20 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7643019
关键词：
ATP-Binding Cassette Transporters Acyl Coenzyme A Adrenal Glands Adrenoleukodystrophy Adult Affect Amino Acids Animal Model Animals Antibodies Antigen Presentation Area Behavioral Biochemical Brain CD8B1 gene Caliber Carbon Cell Death Cell Nucleus Cell physiology Cells Characteristics Chemicals Cholesterol Cholesterol Homeostasis Code Coenzyme A Ligases Cytolysis Cytoplasm Cytoplasmic Granules Cytotoxic T-Lymphocytes Data Development Disease Disease model Drosophila genus Drug Interactions Employee Strikes Enzymes Esters Ethnic group Etiology Eukaryota Evolution Exhibits Exocytosis Family Fatty Acids Fibroblasts Funding Gene Family Genes Genetic Genetic Models Genets Glycerol Goals Hand Heart Hippocampus (Brain)Human Immunity In Situ In Vitro Incidence Individual Knock-out Lead Lesion Ligase Lipids Lorenzo&apos s oil Lytic Maintenance Mass Fragmentography Measures Mediating Medical Membrane Membrane Lipids Metabolic Methods Modeling Molecular Genetics Mono-S Mus Necrosis Nerve Degeneration Nervous System Trauma Nervous system structure Neuraxis Neurodegenerative Disorders Neuroglia Neurons Oligodendroglia Organelles Outcome Study Participant Pathogenesis Pathologic Pathology Patients Penetrance Peptide Hydrolases Pharmaceutical Preparations Phenotype Phospholipids Pigments Plasma Preclinical Drug Evaluation Process Proteins Published Comment RNA Rattus Reiterated Genes Research Role Sarin Schwann Cells Science Site Skin Specificity Staging Structure Study models Supporting Cell Swelling Testing Therapeutic Toxic effect Treatment Protocols Very Long Chain Fatty Acid Work Yeasts base deprivation fatty acid metabolism fly gene function gene therapy in vivo insight leukodystrophy long chain fatty acid male member mutant oxidation peroxisome prevent programs protein function research study response white matter

项目摘要

Adrenoleukodystrophy (ALD) is a rare and oftentimes fatal progressive neurodegenerative disease. The most common form of the disease is X-linked (X-ALD); it occurs equally in all ethnic groups with an estimated incidence of 1:17,000. X-ALD is a clinically heterogeneous disorder, exhibiting incomplete penetrance and variable expressivity. The gene responsible for X-ALD has been cloned and shown to encode a peroxisomal half ATP-binding-cassette transporter (ABCD1). The 745 amino acid ABCD1 protein localizes to the peroxisomal membrane, where like other members of the ABC (ATP-binding cassette) transporter family, it functions to transport very long chain fatty acids (VLCFAs, 22 or more carbons) via their acyl-CoA esters into peroxisomes where they are degraded by ß-oxidation. Indeed, accumulation of saturated VLCFAs is a known biochemical hallmark of X-ALD. All X-ALD patients, including asymptomatic carriers show elevated levels of VLCFAs in the plasma, brain, and adrenal gland. Currently there are no good treatments for ALD, and the precise mechanisms through which VLCFA concentrations cause ALD are still unknown. Moreover, what previous controversial mouse and fly models of disease ignore is the potential redundancy within the transporter and synthetase gene families that control VLCFA metabolism. Thus, to better understand the evolution and overlapping biochemical functions of the many VLCFA synthetases in flies and humans, we turned to double mutant studies in Drosophila. We have shown that the consequences of knocking out duplicated VLCFA synthetase genes (bubblegum [bgm] and double bubble [dbb]) are profound, and have thus generated a potentially powerful animal model for ALD. From the perspective of disease etiology and treatment, our data indicate that bgm dbb –associated neurodegenerative disease is a disease of lipid- and membrane-rich cells, and that accumulation of fatty acids leads to cell death in affected areas of the brain. Here we propose to test whether the bgm dbb mutant accurately models ALD, with a long-term goal to ascertain a better cellular, molecular, genetic, and chemical understanding of ALD. In particular, we will determine whether bgm and dbb have cell autonomous roles in neurodegeneration and identify the cause(s) of cell death in cells of the CNS. In the longer term, we expect these studies will: (1) facilitate identification of other factors (genes) affecting VLCFA metabolism in the brains, and (2) permit screens for drugs effective in the treatment of neurodegeneration and ALD. 2.

肾上腺素肌营养不良（ALD）是一种罕见且通常是致命的进行性神经退行性疾病。该疾病的最常见形式是X连锁（X-ald）；它在所有种族中同样发生，估计事件为1：17,000。 X-Ald是一种临床上异质性疾病，经历了不完整的外观和可变的表达性。负责X-ald的基因已被克隆，并证明可以编码过氧物理体的半结合插管转运蛋白（ABCD1）。 745氨基酸ABCD1蛋白定位于过氧化物体膜，与ABC的其他成员（ATP结合盒）转运蛋白家族一样，它可以通过将非常长的链脂肪酸（VLCFAS，22或更多Carbons）通过其酰基-COA酯化为peroxysomes的蛋白酶酯降解。实际上，饱和VLCFA的积累是X-Ald的已知生化标志。所有X-ALD患者，包括不对称载体，均显示血浆，大脑和肾上腺中VLCFA的水平升高。当前没有对ALD的良好治疗方法，并且VLCFA浓度引起ALD的确切机制仍然未知。此外，以前的浓缩小鼠和疾病模型忽略了控制VLCFA代谢的转运蛋白和合成酶基因家族中的潜在冗余。为了更好地理解苍蝇和人类中许多VLCFA合成酶的进化和重叠的生化功能，我们转向了果蝇中的双重突变研究。我们已经表明，淘汰重复的VLCFA合成酶基因（Bubblegum [BGM]和Double Bubble [DBB]）的后果是深刻的，因此产生了ALD的潜在强大动物模型。从疾病病因和治疗的角度来看，我们的数据表明BGM DBB相关的神经退行性疾病是一种脂质和膜富含膜细胞的疾病，并且脂肪酸的积累导致脑受影响区域的细胞死亡。在这里，我们建议测试BGM DBB突变体是否精确模型ALD，其长期目标是确定对ALD的细胞，分子，遗传和化学理解的更好的细胞，分子，遗传和化学理解。特别是，我们将确定BGM和DBB在神经变性中是否具有细胞自主作用，并确定CNS细胞中细胞死亡的原因。从长远来看，我们预计这些研究将：（1）促进影响大脑中VLCFA代谢的其他因素（基因），以及（2）允许筛查有效治疗神经变性和ALD的药物。 2。