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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.