Illuminating neurodegenerative tauopathy from somatic genomic landscapes of single human brain cells

项目总结/摘要 神经退行性疾病，包括阿尔茨海默病（AD）、原发性tau蛋白病和其他痴呆， 影响了超过650万美国人，给家庭和社会带来了重大挑战。的标志 神经退行性疾病是错误折叠的蛋白质在脑中的典型沉积，具有原发性神经退行性疾病。 显示tau在神经元和神经胶质中积累的tau蛋白病。原发性肝癌细胞功能障碍的基础 tau蛋白病还没有得到很好的理解，强调了扩大生物学研究范围的重要需求。 基于人脑组织单细胞全基因组测序（scWGS）的技术进步， 现在允许检查以前无法访问的大脑中单个细胞的基因组方面。我 我和我的同事发现，AD患者的神经元显示出更大的体细胞单核苷酸 与没有AD的个体相比，在他们的基因组中存在sSNV变体。根据突变特征分析， 体细胞突变的原因在AD中不同，涉及氧化应激和其他信号提示其他 细胞病理学事件。 本研究将评估原发性tau蛋白病背景下的体细胞突变，基于四种互补的 主题.我将研究神经元和神经胶质细胞的全基因组体细胞突变过程， 在一个细胞模型系统中，我们可以解剖特定的贡献者， 突变机制我还将使用单细胞功能研究来探索细胞死亡的机制， 原发性tau蛋白病在整个研究过程中，我将采用新的单细胞细胞病理学方法来研究作用 在体细胞突变和更广泛的疾病机制中的作用。与新的互补方法 scWGS技术，单核分选，以及独特的人体组织和细胞系统资源，我将 研究原发性tau蛋白病中体细胞突变的机制作用。这项工作旨在解决 神经退行性疾病的基本问题，并开发新的方法来识别疾病 机制，具有更好的诊断和治疗选择的广泛应用的潜力。

PROJECT SUMMARY / ABSTRACT Neurodegenerative diseases, which include Alzheimer’s (AD), primary tauopathies, and other dementias, affect more than 6.5 million Americans with significant challenges for families and society. The hallmark of neurodegenerative disease is the stereotypical deposition of misfolded protein in the brain, with primary tauopathies showing tau accumulation in neurons and glia. The basis for cellular dysfunction in primary tauopathies is not well understood, underscoring an important need to broaden the biologic scope of research. Technological advances, based on single-cell whole-genome sequencing (scWGS) on human brain tissue, now allow examination of previously inaccessible aspects of the genome of individual cells in the brain. My colleagues and I have found that neurons in individuals with AD show greater somatic single-nucleotide variants (sSNV) in their genomes than in individuals without AD. From mutational signature analysis, specific causes of somatic mutations differed in AD, implicating oxidative stress and additional signal suggesting other cytopathologic events. This study will assess somatic mutation in the setting of primary tauopathies, based on four complementary themes. I will examine the process of genome-wide somatic mutation in neurons and glia in brain from individuals with primary tauopathy, and in a cellular model system we can dissect specific contributors to mutational mechanisms. I will also use single-cell functional studies to probe mechanisms of cell death in primary tauopathy. Throughout the study, I will use new single-cell cytopathological methods to study the role of tau in somatic mutation and broader disease mechanisms. With complementary approaches of novel scWGS technology, single-nucleus sorting, and unique human tissue and cellular system resources, I will examine the mechanistic role of somatic mutations in primary tauopathy. This work stands to address fundamental questions in neurodegeneration and develop new approaches for identification of disease mechanisms, with the potential for broad application for better diagnostic and therapeutic options.