Effects of frontotemporal dementia-associated Tau mutations on nuclear organization in a Drosophila melanogaster human tauopathy model

项目总结： 额颞性痴呆(FTD)是一种与微管突变相关的神经退行性疾病 结合蛋白Tau。FTD平均发病年龄为49岁，平均预期寿命为8.5岁。临床部 FTD的表现与帕金森氏症、痴呆、颞叶萎缩的患者不同 脑叶和人格改变。目前的治疗方法可以缓解相关行为变化的某些方面 然而，对于FTD，没有可用的治疗方法来减缓进展。由于患者样本的采购是 仅限于死后组织，我们对进展和潜在致病机制的理解 对这种疾病的研究是有限的，要解决这些问题，需要使用模式生物。最近的工作在 模型系统和死后组织已经表明，FTD相关突变体Tau的表达可能导致 改变基因表达的表观遗传修饰。在我们的实验室中，我们使用果蝇来模拟FTD，这使得 美国将进行纵向研究，以观察FTD在整个成人寿命中的进展情况。这表明， 表达FTD相关突变型人Tau(HTau)的成年果蝇具有年龄依赖性神经退行性变 空泡、轴突变化、运动障碍和记忆受损，而表达正常hTau的果蝇则没有。 这证实了我们的模型显示了与变态反应相关的致病表型，并且它提供了 为现在使用这些模型识别致病的分子机制奠定了基础。在这个提案中，我假设 FTD突变体Tau改变了异染色质的分布，从而扰乱了基因表达和染色质结构 产生或促成FTD病理学中所见的行为和神经退行性变的表型。在……里面 此外，我假设基因调控网络将根据FTD突变的不同而不同，因为 突变在临床上是不同的。我建议用以下目的来检验这一假设：(1)使用单细胞组学 评估人类Tau FTD突变如何改变年轻和健康人群染色质的可及性和基因表达 老年成年果蝇脑内异染色质区域定位的研究 HTauK369I FTD果蝇模型，(3)确定新的候选基因在FTD果蝇模型中的作用 通过基因相互作用测试。利用单细胞技术将使我们了解突变牛磺酸是如何 影响大脑中不同的细胞类型，它可能识别特定细胞类型的候选细胞，并导致 开发靶向治疗。

PROJECT SUMMARY: Frontotemporal dementia (FTD) is a neurodegenerative disease associated with mutations in the microtubule binding protein Tau. Average age of FTD onset is 49 years old with a life expectancy of 8.5 years. The clinical presentation of FTD is heterogeneous with patients exhibiting parkinsonism, dementia, atrophy in the temporal lobes, and personality changes. Current treatments can mitigate aspects of the behavioral changes associated with FTD, however, no therapies are available to slow the progression. Since patient sample procurement is restricted to post-mortem tissue, our understanding of the progression and underlying pathogenic mechanisms of this disease is limited, and to address these issues requires the use of model organisms. Recent work in model systems and post-mortem tissue has shown that expression of FTD-associated mutant Tau may lead to epigenetic modifications that alter gene expression. In our lab, we model FTD using Drosophila, which allowed us to conduct longitudinal studies to observe FTD progression throughout the adult lifespan. This revealed that adult Drosophila expressing FTD-associated mutant human Tau (hTau) have age-dependent neurodegenerative vacuoles, axonal changes, locomotion defects and impaired memory while flies expressing normal hTau did not. This confirms that our models show pathogenic phenotypes associated with Tauopathies and it provides the basis to now use these models to identify molecular mechanisms of pathogenicity. In this proposal, I hypothesize that FTD mutant Tau alters heterochromatin distribution, which disrupts gene expression and chromatin structure producing or contributing to the behavioral and neurodegenerative phenotypes seen in FTD pathology. In addition, I hypothesize that the gene regulatory networks will vary depending on the FTD mutation as each mutation is clinically distinct. I propose to test this hypothesis with the following aims: (1) Use single-cell omics to assess how human Tau FTD mutations alter chromatin accessibility and gene expression in the young and aged adult Drosophila brain, (2) Probe nuclear architecture changes by mapping heterochromatin regions in the hTauK369I FTD Drosophila model, (3) Determine the role of novel candidate genes in our FTD Drosophila model through genetic interaction tests. Utilizing single-cell technology will allow us to understand how the mutant Tau affects distinct cell types in the brain and it may identify cell-type-specific candidates, and lead to the development of targeted therapies.