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在 (前) 症状的人类C9ORF72-ALS/FTD大脑器官中,分子病理,发育变化和突触功能障碍

Astrid T van der Geest¹, Channa E Jakobs¹, Tijana Ljubikj¹

¹Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Acta neuropathologica communications

|September 17, 2024

概括

在C9ORF72中,一个六核酸重复扩张 (HRE) 导致ALS/FTD. 来自患者的大脑器官揭示了早期的分子和突触变化,甚至在症状前的携带者中,提供了对疾病发病的洞察力.

科学领域:

神经科学是一个神经科学.
遗传学是一个遗传学.
干细胞生物学干细胞生物学

背景情况:

C9ORF72 六核酸重复扩张 (HRE) 是肌缩侧面硬化症 (ALS) 和前性痴呆症 (FTD) 的主要遗传原因.
大脑的早期结构和连接性变化在症状出现之前发生在C9-ALS/FTD中,但这些表型尚未完全理解.

研究的目的:

通过从C9-ALS/FTD患者和症状前携带者获得的诱导多能干细胞 (iPSC) 衍生脑器官来研究大脑中的早期分子和细胞变化.
了解导致C9-ALS/FTD发病的初始病理,并为治疗策略提供信息.

主要方法:

从C9-ALS/FTD患者,症状前的C9ORF72-HRE携带者和对照患者中生成iPSC衍生的脑器官.
利用单细胞RNA测序,分子和细胞分析以及补丁电生理学来评估有机体表型.

主要成果:

来自C9-ALS/FTD患者的大脑器官表现出所有三个C9-HRE分子病理和发育大小改变.
单细胞RNA测序揭示了改变的细胞类型丰富性,包括减少深层皮质神经元和神经前代分布的变化.
突触结构和功能发生了变化,症状前的携带者表现出C9-HRE分子病理,有不同的下游细胞缺陷.

结论:

大脑器官模型早期C9-ALS/FTD病理,包括分子和突触变化.
预症状携带者表现出分子病理,表明早期的疾病过程.
这些发现突出了3D人类大脑组织中关键的初始病理,这与了解疾病发病和开发疗法有关.

关键词:

这就是ALS.脑子脑子脑子脑子 C9ORF72C9ORF72C9ORF72C9ORF72C9ORF72C9ORF72C9ORF72C9ORF72C9ORF72C9ORF72C9ORF72C9ORF72C9ORF72C9ORF72C9ORF72C9ORF72C9ORF72C9ORF72C9ORF72C9ORF72C9ORF72C9ORF72C9ORF72C9ORF72C 发展发展发展发展发展神经系统的有机体.没有症状的前症状.

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