Genetic Analysis of Neurodegeneration

神经退行性疾病是常见的和破坏性的疾病，这种疾病将变得越来越严重。 随着我们人口的老龄化，这一现象十分普遍。不幸的是，尽管多年来的努力和一些有希望的线索，我们仍然 没有治疗疾病的方法。为研究这些疾病提供了另一种方法 并确定潜在的治疗方法，我们已经率先使用果蝇作为模型系统 研究神经退行性变，特别强调帕金森氏症和阿尔茨海默病。 我们的研究使我们能够在果蝇模型中识别控制神经退化的基因。我们有 随后在脊椎动物模型中证实了这些发现，在死后脑组织中 患者和患者来源的细胞中。在目前的提案中，我们将利用我们之前的进展，通过 从机制细节探讨血影蛋白细胞骨架的改变在促进中的作用 α-突触核病症中的神经变性。具体地说，我们将测试α-突触核蛋白与 该蛋白的锚蛋白结合域，从而干扰自噬小体的运输和成熟。 我们最近开发了一种强大的新α模型--果蝇体内的突触核蛋白毒性。我们以前的 该模型对多巴胺能神经元具有显著的特异性。虽然对探索毒性很有价值 多巴胺神经元是帕金森氏病的一种非常重要的细胞类型，目前存在有限的病理 大规模基因筛查的有限实施。因此，我们创建了一个α-突触核蛋白模型 神经毒性，与年龄相关的神经退行性变明显更为普遍。我们的新型号 促进了基因组规模的遗传筛选的完成，这是果蝇模型的重要优势。 重要的是，我们的新α-突触核素病模型使用了我们开发的双重转录系统， 它允许同时和独立地在神经元和神经胶质细胞中大规模地操纵基因表达。 我们现在可以定义胶质细胞控制α-突触核蛋白毒性的广泛机制。 神经元自主地非细胞的。鉴于越来越多的证据表明神经胶质细胞在 神经退行性疾病，这些研究有可能产生重大影响。

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.