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

项目概要： 额颞叶痴呆是一种与微管突变相关的神经退行性疾病 结合蛋白Tau。FTD发病的平均年龄为49岁，预期寿命为8.5岁。临床 FTD的表现是异质性的，患者表现为帕金森综合征、痴呆、颞叶萎缩， 脑叶和人格改变目前的治疗方法可以减轻与此相关的行为变化的各个方面。 然而，对于FTD，没有可用的治疗来减缓进展。由于患者样本采购是 仅限于死后组织，我们对疾病进展和潜在致病机制的理解 这种疾病的研究是有限的，解决这些问题需要使用模式生物。最近的工作 模型系统和死后组织显示，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，我们使用果蝇模拟FTD， 我们进行纵向研究，以观察FTD在整个成人寿命期间的进展。这揭示了 表达FTD相关突变体人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、运动缺陷和记忆受损，而表达正常hTau的果蝇则没有。 这证实了我们的模型显示出与Tau病相关的致病性表型，并且它提供了 现在使用这些模型来确定致病性的分子机制的基础。在这个提议中，我假设 FTD突变Tau改变异染色质分布，从而破坏基因表达和染色质结构 产生或促成FTD病理学中观察到的行为和神经退行性表型。在 此外，我假设基因调控网络将根据FTD突变而变化， 突变在临床上是不同的。我建议用以下目标来检验这一假设：（1）使用单细胞组学 评估人Tau FTD突变如何改变年轻人的染色质可及性和基因表达， （2）通过绘制老年果蝇脑异染色质区域来探讨核结构的变化， hTauK369 I FTD果蝇模型，（3）确定新候选基因在FTD果蝇模型中的作用 通过基因互动测试。利用单细胞技术将使我们了解突变的Tau 影响大脑中不同的细胞类型，它可以识别细胞类型特异性候选人，并导致 靶向疗法的开发。

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.