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且具有破坏性的疾病，其将变得越来越严重 不幸的是，随着我们的人口老龄化，尽管我们付出了多年的努力并取得了一些有希望的成果，但我们仍然如此。 没有疾病缓解疗法 提供研究这些疾病的替代方法。 和潜在的治疗方法，我们率先确定了使用果蝇作为模型系统 研究神经退行性疾病，特别关注帕金森病和阿尔茨海默病。 我们的研究使我们能够在果蝇模型中识别出控制神经退行性变的基因。 随后在疾病的脊椎动物模型和死后脑组织中验证了这些发现 在当前的提案中，我们将利用我们之前的进展： 详细探索血影蛋白细胞骨架的改变在促进 具体来说，我们将检验 α-突触核蛋白结合的假设。 β-血影蛋白的锚蛋白结合域，从而扰乱自噬体的运输和成熟。 我们最近在果蝇中开发了一种强大的 α-突触核蛋白毒性新模型。 模型对多巴胺能神经元表现出惊人的特异性，同时对于探索对多巴胺能神经元的毒性有价值。 多巴胺神经元是帕金森病的一种非常重要的细胞类型，是目前有限的病理学 因此，我们创建了 α-突触核蛋白模型。 我们的新模型中，年龄依赖性神经变性更为普遍。 促进了基因组规模遗传筛选的完成，这是果蝇模型的重要优势。 重要的是，我们新的 α-突触核蛋白病模型采用了我们开发的双转录系统， 它允许同时和独立地大规模操纵神经元和神经胶质细胞中的基因表达。 我们现在可以定义神经胶质细胞控制 α-突触核蛋白毒性的广泛补充机制 鉴于越来越多的证据表明神经胶质细胞在非细胞自主神经元中发挥着重要作用。 神经退行性疾病，这些研究有可能产生重大影响。