Genetic Analysis of Neurodegeneration

神经退行性疾病的遗传分析

• 批准号: 10665209
• 负责人: MEL B FEANY
• 金额: $ 92.17万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2031-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665209
• 关键词: Affect; Age; Alzheimer' s Disease; Ankyrins; Autophagosome; Autopsy; Binding; Biological Models; Caregivers; Cells; Complement; Cytoskeleton; Disease; Disease model; Drosophila genus; Gene Expression; Genes; Genetic Screening; Genetic Transcription; Goals; Healthcare; Modeling; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Parkinson Disease; Pathology; Patients; Play; Population; Resources; Role; Specificity; Spectrin; System; Testing; Therapeutic; Toxic effect; age related; alpha synuclein; beta Spectrin; brain tissue; cell type; dopaminergic neuron; effective therapy; fly; genetic analysis; genetic manipulation; genome-wide; innovation; neurotoxicity; synucleinopathy

Neurodegenerative diseases are common and devastating disorders, which will become increasingly prevalent as our population ages. Unfortunately, despite years of effort and some promising leads, we still do not have disease-modifying therapies. To provide an alternative approach to studying these disorders and identifying potential therapeutics we have pioneered the use of Drosophila as a model system for studying neurodegeneration, with a particular emphasis on Parkinson’s disease and Alzheimer’s disease. Our studies have allowed us to identify genes controlling neurodegeneration in our fly models. We have subsequently verified these findings in vertebrate models of the diseases, in postmortem brain tissue from patients and in patient-derived cells. In the current proposal we will capitalize on our prior progress by exploring in mechanistic detail the role alterations of the spectrin cytoskeleton play in promoting neurodegeneration in α-synucleinopathies. Specifically, we will test the hypothesis that α-synuclein binds to the ankyrin-binding domain of ß-spectrin and thereby perturbs autophagosome transport and maturation. We have recently developed a powerful new model of α-synuclein toxicity in Drosophila. Our previous model showed striking specificity for dopaminergic neurons. While valuable for exploring toxicity to dopamine neurons, a very important cell type for Parkinson’s disease, the restricted pathology present limited implementation of large-scale genetic screens. We have therefore created a model of α-synuclein neurotoxicity in which age-dependent neurodegeneration is significantly more widespread. Our new model has facilitated completion of a genome-scale genetic screen, an important strength of Drosophila models. Importantly, our new α-synucleinopathy model employs a dual transcriptional system we have developed, which allows simultaneous and independent manipulation of gene expression, at scale, in neurons and glia. We can now define the broad complement of mechanisms by which glia control toxicity of α-synuclein in neurons non-cell autonomously. Given the growing evidence for an important role for glia in neurodegenerative disease, these studies have the potential for significant impact.

神经退行性疾病是常见和毁灭性疾病，这将变得越来越多 随着我们的人口年龄而流行。不幸的是，多斯特的多年努力和一些有前途的潜在客户，我们仍然 没有改良疾病的疗法。提供一种研究这些疾病的替代方法 并确定潜在的疗法，我们率先使用果蝇作为模型系统 研究神经变性，特别着重于帕金森氏病和阿尔茨海默氏病。 我们的研究使我们能够鉴定控制飞行模型中神经变性的基因。我们有 随后在疾病的脊椎动物模型中验证了这些发现， 患者和患者衍生细胞。在当前的提案中，我们将通过 探索机械详细的探索光谱细胞骨架在促销中的作用改变 α-突触核疾病中的神经变性。具体而言，我们将检验以下假设：α-核蛋白与 β-光谱蛋白的Ankyrin结合结构域，从而使自噬体的运输和成熟度掩盖。 我们最近开发了果蝇中α-突触核蛋白毒性的强大新模型。我们的先前 模型显示了多巴胺能神经元的惊人特异性。虽然对于探索毒性很有价值 多巴胺神经元，一种非常重要的帕金森氏病细胞类型，存在的病理受限 大规模遗传筛查的实施有限。因此，我们创建了α-突触核蛋白的模型 神经毒性依赖年龄的神经变性明显更宽度。我们的新模型 已经准备好完成基因组规模遗传筛选，这是果蝇模型的重要强度。 重要的是，我们的新α-突触核模型采用了我们已经开发的双重转录系统， 它允许在神经元和神经胶质中进行简单而独立的基因表达操纵。 现在，我们可以确定胶质控制α-突触核蛋白中的胶质毒性的广泛机制 神经元非单独自主。考虑到越来越多的证据表明神经胶质在 神经退行性疾病，这些研究有可能产生重大影响。