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 神经退行性疾病袭击中年人，就像他们达到完整的家庭，财务和职业生涯 潜力最初被认为是非常不同的，FTLD和ALS现在被认为有许多临床， 病理和遗传特征，但它们共享和独特电路的机械基础仍然存在 在分子水平上是未知的全基因组关联研究（GWAS）发现了多种常见的 弱效应变体，但绝大多数是非编码的，因此很难识别其靶基因， 它们作用的细胞类型。为了应对这一挑战，在目标1中，我们系统地分析了转录 FTLD和ALS患者的表观基因组改变在单细胞分辨率使用死后脑 样品在目标2中，我们整合了得到的数据集来研究遗传，表观基因组， 转录和细胞签名的FTLD和ALS，并研究共同和不同的基因， 在每一个改变的途径，以预测新的治疗目标。在目标3中，我们验证了分子和细胞 这些目标的影响，使用高通量定向扰动实验和细胞自主和 非自主表型由我们预测的途径指导，我们传播我们所有的结果， 社区由此产生的数据集，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，以及新的共同和独特的电路 治疗目标

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.