Single-Cell Transcriptional and Epigenomic Dissection to Identify Therapeutic Targets for ALS and FTD

摘要 额颞叶变性(FTLD)和肌萎缩侧索硬化症(ALS)是毁灭性的和致命的 神经退行性疾病在中年人达到完全的家庭、经济和职业生涯时袭击他们 潜力。最初被认为是相当不同的FTLD和ALS，现在被认为共享许多临床， 病理性的和遗传的特征，但它们共享和不同的电路的机械基础仍然存在 在分子水平上未知。全基因组关联研究(GWAS)发现了多个共同的 弱效变异体，但绝大多数是非编码的，这使得识别它们的目标基因和 它们活动的细胞类型。为了应对这一挑战，在目标1中，我们系统地描述了转录 以及FTLD和ALS患者死后脑单细胞分辨率的表观基因组改变 样本。在目标2中，我们整合得到的数据集来研究遗传、表观基因组学、 FTLD和ALS的转录和细胞特征，并研究共同和不同的基因和 每一种都改变了通路，以预测新的治疗靶点。在目标3中，我们验证了分子和细胞 使用高通量定向微扰实验和细胞自主和 由我们预测的路径引导的非自主表型，我们将所有结果传播给 社区。生成的数据集、分析和验证的目标将提供宝贵的资源 了解FTLD和ALS的作用机制，以及通向新的和独特的电路 治疗靶点。

Abstract Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are devastating and fatal neurodegenerative diseases that strike middle-aged adults just as they reach full familial, financial and career potential. Initially thought to be quite distinct, FTLD and ALS are now recognized to share many clinical, pathological, and genetic signatures, but the mechanistic basis of their shared and distinct circuitry remains unknown at the molecular level. Genome-wide association studies (GWAS) have uncovered multiple common weak-effect variants, but the vast majority are non-coding, making it difficult to identify their target genes and the cell types where they act. To address this challenge, in Aim 1, we systematically profile the transcriptional and epigenomic alterations of FTLD and ALS patients at single-cell resolution using post-mortem brain samples. In Aim 2, we integrate the resulting datasets to study the link between genetic, epigenomic, transcriptional, and cellular signatures of FTLD and ALS, and to study the common and distinct genes and pathways altered in each, to predict new therapeutic targets. In Aim 3, we validate the molecular and cellular effects of these targets using high-throughput directed perturbation experiments and both cell-autonomous and non-autonomous phenotypes guided by our predicted pathways, and we disseminate all our results to the community. The resulting datasets, analyses, and validated targets will provide an invaluable resource to understand the mechanisms of action of FTLD and ALS, and the common and unique circuitry towards new therapeutic targets.