有症状的人类 C9ORF72-ALS/FTD 脑类器官的分子病理学、发育变化和突触功能障碍。
Molecular pathology, developmental changes and synaptic dysfunction in (pre-) symptomatic human C9ORF72-ALS/FTD cerebral organoids.
发表日期：2024 Sep 18
作者：
Astrid T van der Geest, Channa E Jakobs, Tijana Ljubikj, Christiaan F M Huffels, Marta Cañizares Luna, Renata Vieira de Sá, Youri Adolfs, Marina de Wit, Daan H Rutten, Marthe Kaal, Maria M Zwartkruis, Mireia Carcolé, Ewout J N Groen, Elly M Hol, Onur Basak, Adrian M Isaacs, Henk-Jan Westeneng, Leonard H van den Berg, Jan H Veldink, Domino K Schlegel, R Jeroen Pasterkamp
来源：
Acta Neuropathologica Communications
摘要：
C9ORF72 中的六核苷酸重复扩增 (HRE) 是肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 最常见的遗传原因。人脑成像和实验研究表明，即使在症状出现之前，C9-ALS/FTD 的大脑结构和连接性也发生了早期变化。由于这些早期疾病表型仍未完全了解，我们从 C9-ALS/FTD 患者、症状前 C9ORF72-HRE (C9-HRE) 携带者和对照中生成了 iPSC 衍生的脑类器官模型。我们的工作揭示了 C9-ALS/FTD 患者的脑类器官中存在所有三种 C9-HRE 相关分子病理学和发育阶段依赖的大小表型。此外，单细胞 RNA 测序还发现了 C9-ALS/FTD 类器官中细胞类型丰度和分布的变化，包括深层皮质神经元数量和神经祖细胞分布的减少。此外，分子和细胞分析以及膜片钳电生理学检测到突触结构和功能的各种变化。有趣的是，来自所有症状前 C9-HRE 携带者的类器官都显示出 C9-HRE 分子病理学，而在不同症状前 C9-HRE 病例中，检测到更多下游细胞缺陷（如 C9-ALS/FTD 模型中发现）的程度各不相同。总之，这些结果揭示了 3D 人脑组织组织和 C9-ALS/FTD 突触连接的早期变化，这些变化可能构成对于理解疾病发作和治疗策略设计至关重要的初始病理。© 2024。作者。
A hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Human brain imaging and experimental studies indicate early changes in brain structure and connectivity in C9-ALS/FTD, even before symptom onset. Because these early disease phenotypes remain incompletely understood, we generated iPSC-derived cerebral organoid models from C9-ALS/FTD patients, presymptomatic C9ORF72-HRE (C9-HRE) carriers, and controls. Our work revealed the presence of all three C9-HRE-related molecular pathologies and developmental stage-dependent size phenotypes in cerebral organoids from C9-ALS/FTD patients. In addition, single-cell RNA sequencing identified changes in cell type abundance and distribution in C9-ALS/FTD organoids, including a reduction in the number of deep layer cortical neurons and the distribution of neural progenitors. Further, molecular and cellular analyses and patch-clamp electrophysiology detected various changes in synapse structure and function. Intriguingly, organoids from all presymptomatic C9-HRE carriers displayed C9-HRE molecular pathology, whereas the extent to which more downstream cellular defects, as found in C9-ALS/FTD models, were detected varied for the different presymptomatic C9-HRE cases. Together, these results unveil early changes in 3D human brain tissue organization and synaptic connectivity in C9-ALS/FTD that likely constitute initial pathologies crucial for understanding disease onset and the design of therapeutic strategies.© 2024. The Author(s).