New Drosophila Model of VPS35 Parkinsonism

VPS35帕金森病的新果蝇模型

• 批准号: 8773498
• 负责人: Katerina Venderova
• 金额: $ 6.46万
• 依托单位: UNIVERSITY OF THE PACIFIC-STOCKTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8773498
• 关键词: Affect; Alzheimer' s Disease; Animal Model; Applications Grants; Autophagocytosis; Autophagosome; Cell physiology; Cells; Cessation of life; Complex; Data; Development; Disease; Disease Progression; Dominant-Negative Mutation; Drosophila eye; Drosophila genus; Eye; Future; Generations; Genes; Genetic Models; Genetic Screening; Genets; Goals; LRRK2 gene; Lead; Manuscripts; Mediating; Modeling; Molecular; Mutation; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Outcome; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Preclinical Drug Evaluation; Process; Proteins; Proteomics; Publishing; Research; Role; Rotenone; Sorting - Cell Movement; Testing; Therapeutic Intervention; Time; Transgenic Organisms; Vacuolar Protein Sorting; Work; Yeasts; base; cell type; disease phenotype; dopaminergic neuron; fly; gain of function; genetic risk factor; improved; in vivo; inhibitor/antagonist; insight; knock-down; locomotor deficit; mutant; novel; overexpression; public health relevance; response; tool; trafficking

DESCRIPTION (provided by applicant): There is a growing unmet need for a better treatment of Parkinson's disease (PD). Our goal is to improve the understanding of molecular pathways involved in the pathogenesis of this neurodegenerative process, to ultimately find new pharmacological targets for a disease-modifying therapeutic intervention. Identification of Vacuolar protein sorting 35 (VPS35) as the latest autosomal dominant causative gene of PD highlighted the role of retromer and retromer-dependent trafficking in PD. However how exactly VPS35 contributes to PD pathogenesis is entirely unknown, and at present there is no animal model of VPS35 parkinsonism. Therefore the goal of this grant application is to develop the first animal model of VPS35 parkinsonism. Specifically, we are planning to generate a new transgenic Drosophila line that will allow expressing the D647N mutant of Drosophila Vps35 (equivalent to the pathogenic D620N mutation identified in PD patients). We anticipate that expressing Vps35(D647N) in dopaminergic neurons will lead to neuronal death, locomotor deficits, increased sensitivity to rotenone, and impaired autophagy - a cellular process recently implicated in the pathogenesis of several neurodegenerative disorders, including PD. Specifically, we postulate that Vps35 is required for efficient autophagy, and that expressing Vps35(D647N) will impair the autophagic response. In addition, we hypothesize that Vps35(D647N) mutant flies will present with an eye phenotype, similar to many other models of neurodegenerative disorders, including our LRRK2 transgenic fly. Characterization of an eye phenotype would make this animal model valuable in future genetic screens or drug screens. This proposal will provide a new valuable tool to study PD pathogenesis in vivo, one that will help elucidate the mechanisms by which this newly discovered retromer-dependent pathway contributes to PD pathology. This may significantly advance the field of PD and other neurodegenerative disorders, and may uncover new pharmacological targets for a better treatment.

描述（由申请人提供）：对帕金森病（PD）的更好治疗的需求不断增长。我们的目标是提高对参与这种神经退行性过程的发病机制的分子途径的理解，最终找到新的药理学靶点用于疾病修饰治疗干预。最新的常染色体显性PD致病基因VPS 35的鉴定强调了逆转录聚合物和逆转录聚合物依赖的运输在PD中的作用。然而，VPS 35究竟如何参与PD发病机制尚不清楚，目前还没有VPS 35帕金森病的动物模型。因此，这项拨款申请的目标是开发第一个VPS 35帕金森病动物模型。具体而言，我们计划产生一种新的转基因果蝇系，该果蝇系将允许表达果蝇Vps 35的D 647 N突变体（相当于在PD患者中鉴定的致病性D 620 N突变）。我们预期在多巴胺能神经元中表达Vps 35（D 647 N）将导致神经元死亡、运动缺陷、对鱼藤酮的敏感性增加和受损的自噬-最近涉及几种神经退行性疾病（包括PD）的发病机制的细胞过程。具体地说，我们假设Vps 35是有效的自噬所必需的，并且表达Vps 35（D 647 N）将损害自噬反应。此外，我们假设Vps 35（D 647 N）突变果蝇将呈现眼睛表型，类似于许多其他神经退行性疾病模型，包括我们的LRRK 2转基因果蝇。眼睛表型的表征将使该动物模型在未来的遗传筛选或药物筛选中具有价值。这一建议将提供一个新的有价值的工具来研究PD的发病机制在体内，一个将有助于阐明这种新发现的逆转录依赖性途径有助于PD病理的机制。这可能会显着推进PD和其他神经退行性疾病的领域，并可能发现新的药理学靶点，以获得更好的治疗。