Cell Type and Regional Vulnerability in Frontotemporal Dementia

额颞叶痴呆的细胞类型和区域脆弱性

• 批准号: 10292573
• 负责人: SALLY TEMPLE
• 金额: $ 209.44万
• 依托单位: REGENERATIVE RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292573
• 关键词: 26S proteasome; 3-Dimensional; Address; Affect; Alzheimer' s Disease; Behavioral; Brain; Brain region; Cell Communication; Cell Death; Cell Line; Cells; Cerebral cortex; Cerebrum; Cognitive deficits; Collection; Complex; Computer software; Corpus striatum structure; Disease; Engineering; Familial Dementias; Family; Frontotemporal Dementia; Functional disorder; Gene Expression; Glutamates; Goals; Health; Human; Image; Impairment; Induced pluripotent stem cell derived neurons; Interneurons; Intrabody; Knowledge; Label; Language Disorders; Lead; MAPT gene; Midbrain structure; Modeling; Molecular; Mutation; Neurons; Organoids; Parkinsonian Disorders; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Population; Prefrontal Cortex; Production; Prosencephalon; RNA Splicing; Reporter; Research; Resistance; Role; Substantia nigra structure; System; Tauopathies; Temporal Lobe; Testing; Time; Ubiquitin; Variant; Western Blotting; brain cell; cell type; dopaminergic neuron; early onset; frontal lobe; improved; induced pluripotent stem cell; multicatalytic endopeptidase complex; mutant; neuron loss; prevent; proteostasis; response; single-cell RNA sequencing; stressor; tau Proteins; tau aggregation; therapy development; time use; transcriptomics

Project Summary/Abstract A key question in tauopathy research is why some brain cell populations are significantly affected while others are relatively spared. The long-term goal of this study is to understand this differential cell vulnerability and use the knowledge to develop therapies that protect neural cells from tauopathy-related degeneration. Mutations in the MAPT gene that encodes Tau commonly cause extensive pathology in the forebrain, with significant loss of frontal and temporal lobe cerebral cortical cells leading to behavioral, language and cognitive deficits. However, a subset of MAPT mutations also cause significant degeneration of midbrain dopaminergic neurons in the substantia nigra contributing to a parkinsonism phenotype. Furthermore, these cells are connected: midbrain dopaminergic neurons widely innervate the prefrontal cortex and are reciprocally innervated via cortico-striatal-nigral circuits. Why specific MAPT mutations significantly affect the midbrain in addition to cortex while others do not, and how connectivity between these regions with the potential for pathological tau spread may be involved, represent significant gaps in knowledge that we will address in this proposed study. Over the past few years, we have helped create a large iPSC line collection from patients with familial dementia due to mutations in the MAPT gene, including isogenic controls. Phenotypic analyses show MAPT mutant and control iPSC-derived cerebral cortical cells are initially phenotypically similar but develop differences with maturation that include increased tau aggregation, tau hyperphosphorylation and vulnerability to several stressors, associated with the mutation. However, to date, studies comparing forebrain and midbrain cell population responses to MAPT mutations that differentially affect these brain regions have not been done. Such comparisons have the potential to reveal common and unique molecular mechanisms that underlie cell vulnerability. Our approach is to use human iPSC-derived 3D organoids, which recapitulate complex cell-cell interactions in a human cell system and enable long-term culture over several months. We will create cortical and midbrain organoids from two MAPT mutations that primarily affect cortex and two that affect both cortex and midbrain, versus respective isogenic controls. In Aim 1 we will examine the impact of these MAPT mutations on cell populations and gene expression over time using single cell transcriptomics to define how diverse cell types respond to each mutation. In Aim 2, we will create assembloids of cortical and midbrain organoids to model the circuitry between the regions and determine whether this connectivity alters patterns of cell vulnerability and enables the spread of pathological tau from one region to another, depending on specific MAPT mutation. In Aim 3 we will probe the impact of stimulating tau degradation on differential cell vulnerability in cerebral cortex and midbrain.

项目摘要/摘要 陶氏病研究中的一个关键问题是，为什么有些脑细胞群体受到显着影响 相对幸免。这项研究的长期目标是了解这种差分细胞脆弱性并使用 开发保护神经细胞免受陶氏病与变性的疗法的知识。 编码tau的MAPT基因中的突变通常会在前脑中引起广泛的病理， 额叶和颞叶大脑皮质细胞的大量损失导致行为，语言和 认知缺陷。但是，MAPT突变的一部分也会引起中脑的显着变性 黑质中的多巴胺能神经元促成帕金森氏症表型。此外，这些细胞 已连接：中脑多巴胺能神经元广泛支配前额叶皮层，并相互依赖 通过皮质 - 纹状体二象回路支配。为什么特定的MAPT突变显着影响中脑 除了皮层，而其他皮质没有，以及这些区域之间的连通性如何 可能涉及病理性的tau蔓延，代表了我们将在此解决的大量知识差距 拟议的研究。 在过去的几年中，我们帮助创建了家族患者的大型IPSC系列收集 由于MAPT基因中的突变，包括同基因对照。表型分析显示MAPT 突变体和对照IPSC衍生的脑皮质细胞最初在表型上相似，但会产生差异 随着tau聚集的增加，tau高磷酸化和几个脆弱性包括成熟 压力源，与突变有关。但是，迄今为止，比较前脑和中脑细胞的研究 尚未做到对差异影响这些大脑区域的MAPT突变的人口反应。这样的 比较有可能揭示基于细胞的常见和独特的分子机制 脆弱性。 我们的方法是使用人类IPSC衍生的3D器官，该器官概括了复杂的细胞细胞 在人类细胞系统中的相互作用，并在几个月内实现长期培养。我们将创建皮质 来自两个MAPT突变的中脑类器官，主要影响皮层和两个影响皮层和两种影响皮层和 中脑，与各自的同源控制。在AIM 1中，我们将研究这些MAPT突变对 使用单细胞转录组学来定义各种细胞类型的细胞群体和基因表达 响应每个突变。在AIM 2中，我们将创建皮质和中脑器官的组合物，以建模 区域之间的电路并确定这种连接性是否改变了细胞脆弱性的模式和 取决于特定的MAPT突变，使病理TAU从一个区域传播到另一个区域。目标 3我们将探测刺激tau降解对脑皮质和差异细胞脆弱性的影响 中脑。