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.

项目总结/摘要 tau蛋白病研究中的一个关键问题是为什么一些脑细胞群受到显着影响，而另一些脑细胞群受到显着影响。 相对来说是不多的。这项研究的长期目标是了解这种差异细胞的脆弱性和使用 开发保护神经细胞免受tau蛋白病相关变性的疗法的知识。 编码Tau的MAPT基因的突变通常会导致前脑的广泛病变， 额叶和颞叶大脑皮质细胞严重丧失，导致行为、语言和 认知缺陷然而，MAPT突变的一个子集也会导致中脑的显著变性， 黑质中的多巴胺能神经元导致帕金森综合征表型。此外，这些细胞 中脑多巴胺能神经元广泛支配前额皮质， 由皮质-纹状体-黑质回路支配。为什么特定的MAPT突变会显著影响中脑 除了皮层，而其他人没有，以及这些区域之间的连接如何与潜在的 可能涉及病理性tau传播，代表了我们将在本文中解决的知识上的重大差距 建议的研究。 在过去的几年里，我们帮助从家族性白血病患者中建立了大量的iPSC细胞系。 MAPT基因突变导致的痴呆，包括同基因对照。表型分析显示MAPT 突变体和对照iPSC衍生的大脑皮层细胞最初在表型上相似，但发展出差异 随着成熟，包括增加的tau聚集、tau过度磷酸化和对几种 与突变相关的应激源然而，迄今为止，比较前脑和中脑细胞的研究， 对不同影响这些脑区域的MAPT突变的群体反应尚未完成。等 比较有可能揭示共同和独特的分子机制， 易损性. 我们的方法是使用人类iPSC衍生的3D类器官，其重现了复杂的细胞-细胞 在人类细胞系统中的相互作用，并使长期培养超过几个月。我们会在大脑皮层 和中脑类器官，来自两个主要影响皮质的MAPT突变和两个影响皮质和 中脑，与各自的同基因对照。在目标1中，我们将研究这些MAPT突变对 细胞群体和基因表达随时间的变化，使用单细胞转录组学来定义不同的细胞类型 对每一个突变作出反应。在目标2中，我们将创建皮质和中脑类器官的类神经元来模拟 区域之间的电路，并确定这种连接是否改变了细胞脆弱性的模式， 使病理性tau蛋白从一个区域扩散到另一个区域，这取决于特定的MAPT突变。在Aim中 我们将探索刺激tau蛋白降解对大脑皮层中差异细胞脆弱性的影响， 中脑