Characterising day 90 human C9ORF72-ALS/FTD cerebral organoids at single cell level

A hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Human imaging and experimental studies hint at early changes in the brain in C9-ALS/FTD, which remain poorly understood. To define these changes, we used cerebral organoid models derived from C9-ALS/FTD patients and controls to create a single cell RNA sequencing dataset at day 90. Together, these dataset will help to shed light on initial pathologies crucial for understanding disease onset and the design of therapeutic strategies. Overall design: iPSC derive cerebral organoids were generated as reported previously (Lancaster & Knoblich, 2014; Ormel et al., 2018). To study the cell types present in day 90, single cell RNA sequencing (scRNA-seq) was performed on HC (n=3 lines) and C9-ALS/FTD (n=3 lines) organoids

C9ORF72基因的六核苷酸重复扩增（hexanucleotide repeat expansion, HRE）是肌萎缩侧索硬化症（amyotrophic lateral sclerosis, ALS）与额颞叶痴呆（frontotemporal dementia, FTD）最常见的遗传致病因素。现有人类影像学及实验研究提示，C9-ALS/FTD患者的脑部存在早期病理改变，但此类改变的具体机制尚未得到充分阐释。为明确此类早期病理变化，本研究利用源自C9-ALS/FTD患者与健康对照的大脑类器官模型，构建了培养至第90天的单细胞RNA测序（single cell RNA sequencing, scRNA-seq）数据集。本数据集将有助于揭示疾病起始阶段的关键病理特征，为阐明疾病发病机制与开发治疗策略提供重要依据。实验设计：按照既往报道的方法（Lancaster & Knoblich, 2014; Ormel et al., 2018）构建诱导多能干细胞（induced pluripotent stem cell, iPSC）来源的大脑类器官。为分析培养至第90天的类器官中的细胞类型组成，本研究对健康对照（healthy control, HC，n=3株细胞系）与C9-ALS/FTD组（n=3株细胞系）的类器官开展了单细胞RNA测序。