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A Drosophila model for studying mechanisms of Gaucher's disease and synucleinopathies

用于研究戈谢病和突触核蛋白病机制的果蝇模型

基本信息

批准号：
9351579
负责人：
Leo J Pallanck
金额：
$ 32.77万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2020-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9351579
关键词：
Accounting Acids Address Biological Cells Cessation of life Clinic Clinical Coupled Data Defect Disease Drosophila genus Enhancers Enzymes Exhibits Foundations Functional disorder Gaucher Disease Genes Genetic Genetic Screening Genotype Glucosylceramides Impairment Incidence Inherited Lead Lewy Bodies Lewy Body Dementia Lipids Literature Longevity Lysosomes Measures Mediating Memory impairment Methods Midbrain structure Minority Modeling Movement Disorders Mutation Nature Nerve Degeneration Nervous system structure Neuraxis Neurologic Neurologic Deficit Neurologic Symptoms Neurons Parkinson Disease Pathogenesis Patients Penetrance Phenotype Proteins Proteomics Risk Risk Assessment Sphingolipids Study models Symptoms Testing Therapeutic Intervention Visceral Work alpha synuclein dietary manipulation disorder risk dopaminergic neuron experimental study gain of function genetic association genetic manipulation glucosidase glucosylceramidase insight locomotor deficit loss of function lysosomal proteins macrophage mouse model mutation carrier new therapeutic target novel protein aggregate protein degradation public health relevance synucleinopathy targeted treatment therapy development

项目摘要

DESCRIPTION (provided by applicant): Gaucher's disease (GD), the most common lysosomal storage disorder, is caused by recessively inherited mutations in the glucosidase, beta, acid (GBA1) gene, which encodes glucocerebrosidase, a lysosomal enzyme that catalyzes the breakdown of the sphingolipid glucosylceramide. GD encompasses a wide spectrum of clinical symptoms, including severe and untreatable neurological abnormalities. Over the past ten years it has become increasingly clear that patients with GD also have a dramatically elevated risk of Parkinson's disease (PD), a common movement disorder characterized by the death of dopaminergic neurons in the midbrain and the accumulation of intracellular neuronal protein aggregates known as Lewy bodies. More recently, this finding has led to the discovery that heterozygous mutations in GBA1 are the most common genetic association with PD and Lewy body dementia (LBD), possibly accounting for 7-10% of these diseases. The mechanisms by which GBA1 mutations cause neurological symptoms of GD, and increase the risk of PD and LBD, are poorly understood. We hypothesize that the neurological symptoms of GD derive from the lysosomal accumulation of glucosylceramide, and a consequent defect in the degradative capacity of the lysosome. We further hypothesize that mutations in GBA1 increase the risk for PD and LBD by impairing the lysosomal degradation of α-synuclein protein, a major component of the Lewy body aggregates that define both of these diseases. Finally, we hypothesize that genetic modifiers largely account for the poor genotype-phenotype correlation observed in GD and the low penetrance of GBA1 mutations in PD and LBD. To explore these hypotheses, we have created a Drosophila model of glucocerebrosidase deficiency that exhibits shortened lifespan, locomotor and memory deficits, neurodegeneration, and accumulation of protein aggregates. We propose to use our Drosophila model of glucocerebrosidase deficiency, as well as an existing mouse model of glucocerebrosidase deficiency, to pursue three aims. First, we will test the hypothesis that lysosomal glucosylceramide accumulation is responsible for the phenotypes of our Drosophila model of glucocerebrosidase deficiency. Second, we will test the hypothesis that glucocerebrosidase deficiency impairs lysosomal protein degradation, including the degradation of α-synuclein. Third, we will conduct a genetic screen to identify novel modifiers of the phenotypes caused by glucocerebrosidase deficiency. Our work will contribute to a mechanistic understanding of GD, PD and LBD, and this insight will facilitate risk assessment in the clinic and provide a foundation for the development of treatments.

描述（由申请人提供）：戈谢病（GD）是最常见的溶酶体储存疾病，由葡萄糖苷酶β酸（GBA 1）基因的隐性遗传突变引起，该基因编码葡萄糖脑苷脂酶，一种催化分解的溶酶体酶。鞘脂葡萄糖神经酰胺。GD包括广泛的临床症状，包括严重和无法治疗的神经系统异常。在过去的十年中，越来越清楚的是，GD患者患帕金森病（PD）的风险也显著升高，帕金森病是一种常见的运动障碍，其特征在于中脑中多巴胺能神经元的死亡和称为路易体的细胞内神经元蛋白质聚集体的积累。最近，这一发现导致人们发现GBA 1中的杂合突变是与PD和路易体痴呆（LBD）最常见的遗传相关性，可能占这些疾病的7-10%。GBA 1突变引起GD神经系统症状并增加PD和LBD风险的机制尚不清楚。我们假设GD的神经症状来自于葡萄糖神经酰胺的溶酶体积累，以及溶酶体降解能力的缺陷。我们进一步假设GBA 1突变通过损害α-突触核蛋白的溶酶体降解增加PD和LBD的风险，α-突触核蛋白是定义这两种疾病的路易体聚集体的主要成分。最后，我们假设遗传修饰在很大程度上解释了GD中观察到的基因型-表型相关性差以及PD和LBD中GBA 1突变的低突变率。为了探索这些假设，我们建立了一个葡萄糖脑苷脂酶缺乏的果蝇模型，该模型表现出寿命缩短、运动和记忆缺陷、神经变性和蛋白质聚集体积累。我们建议使用我们的果蝇模型的葡萄糖脑苷脂酶缺乏症，以及现有的小鼠模型的葡萄糖脑苷脂酶缺乏症，追求三个目标。首先，我们将测试的假设，溶酶体葡糖神经酰胺积累是负责我们的果蝇模型的葡萄糖脑苷脂酶缺乏症的表型。其次，我们将检验葡萄糖脑苷脂酶缺乏会损害溶酶体蛋白降解（包括α-突触核蛋白降解）的假设。第三，我们将进行遗传筛选，以确定葡萄糖脑苷脂酶缺乏引起的表型的新修饰剂。我们的工作将有助于对GD，PD和LBD的机制的理解，这种见解将有助于临床风险评估，并提供基础用于治疗的发展。