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

额颞叶痴呆相关 Tau 突变对果蝇人类 tau 病模型核组织的影响

基本信息

批准号：
10597996
负责人：
Eve Lowenstein
金额：
$ 4.77万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10597996
关键词：
Actins Address Adult Affect Age Aging Apoptosis Architecture Atlases Atrophic Autopsy Axon Behavioral Binding Proteins Biological Models Brain Candidate Disease Gene Cell Death Cell Nucleus Cells Chromatin Chromatin Structure Chromium Clinical Code Computer Analysis Cyclic AMP-Dependent Protein Kinases Data Defect Dementia Detection Development Disease Disease Progression Drosophila genus Drosophila melanogaster Elderly Enhancers Epigenetic Process Exhibits FMNL2 gene Frontotemporal Dementia Gene Expression Gene Expression Regulation Genes Genetic Genomics Heterochromatin Histologic Histones Human Knock-in Life Expectancy Link Locomotion Longevity Longitudinal Studies Lysine Maps Memory Memory impairment Methylation Microtubules Modeling Modification Molecular Molecular Probes Morphologic artifacts Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Nuclear Lamina Parkinsonian Disorders Pathogenicity Pathology Patients Personality Phenotype Proteins Relaxation Resolution Role Sampling System Tauopathies Temporal Lobe Testing Tissues Toxic effect Vacuole Work age related aged axon growth behavior change behavioral phenotyping cell type chromatin immunoprecipitation epigenetic profiling experimental analysis experimental study fly gene regulatory network genetic manipulation heterochromatin-specific nonhistone chromosomal protein HP-1 imaging study in vivo Model insight knock-down longitudinal analysis model organism mutant neurodegenerative phenotype normal aging novel overexpression prevent promoter single cell technology single-cell RNA sequencing targeted treatment tau Proteins tau mutation therapy development

项目摘要

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.

项目概要：额颞叶痴呆 (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，预期寿命为 8.5 岁。临床上 FTD 的表现各不相同，患者表现出帕金森病、痴呆、颞叶萎缩叶和性格变化。目前的治疗可以减轻相关行为变化的各个方面然而，对于 FTD，没有任何疗法可以减缓进展。由于患者样本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这种疾病的研究是有限的，解决这些问题需要使用模型生物。最近的工作于模型系统和死后组织表明，FTD 相关突变 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，这使得我们进行纵向研究来观察 FTD 在整个成人寿命中的进展情况。这表明表达 FTD 相关突变人类 Tau (hTau) 的成年果蝇患有年龄依赖性神经退行性疾病空泡、轴突变化、运动缺陷和记忆受损，而表达正常 hTau 的果蝇却没有。这证实了我们的模型显示了与 Tau蛋白病相关的致病表型，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。在这个提案中，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 病理学中所见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，因为每个突变在临床上是明显不同的。我建议通过以下目标来检验这一假设：（1）使用单细胞组学评估人类 Tau FTD 突变如何改变年轻人和年轻人的染色质可及性和基因表达老年果蝇大脑，（2）通过绘制异染色质区域来探测核结构的变化 hTauK369I FTD 果蝇模型，(3) 确定新候选基因在我们的 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能够了解突变 Tau 蛋白如何影响大脑中不同的细胞类型，它可以识别特定细胞类型的候选者，并导致靶向治疗的发展。