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人类iPSC4R病模型揭示了传播的修饰剂

Celeste Parra Bravo¹, Alice Maria Giani², Jesus Madero-Perez²

¹Helen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA; Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY 10021, USA.

|April 6, 2024

概括

研究人员开发了一种人类干细胞模型来研究一种神经退行性疾病. 该模型成功复制了关键疾病特征,并确定了UFMylation级联作为tau传播的潜在治疗目标.

科学领域:

神经科学
干细胞生物学
遗传学

背景情况:

病,包括渐进性超核性 (PSP) 和阿尔茨海默病 (AD),是年龄相关的神经退行性疾病,其机制尚不清楚.
现有的人类模型往往无法完全回顾病态,阻碍了疾病病理学和治疗发展的研究.

研究的目的:

设计一种由人类诱导的多能干细胞 (hiPSC) 衍生的神经元模型,表达4R Tau,包括P301S MAPT突变,以研究病.
确定种植诱导的tau传播和tau病的遗传修饰剂和治疗点.

主要方法:

产生表达 4R Tau 和 P301S 突变 Tau 的 hiPSC 衍生神经元系.
通过在分化神经元中播种状纤维来诱导状.
查CRISPR干扰 (CRISPRi) 以确定tau的遗传修饰者.
在患者衍生的脑组织和细胞模型中分析UFMylation级联变化.

主要成果:

工程神经元表现出渐进的tau包容,转录的签名,自积累和神经元活动减少,反映出tau病的特征.
确定了500多种tau传播的基因修饰剂,包括VPS29和UFMylation级联基因.
在PSP和AD大脑中发现UFMylation级联被改变,其抑制抑制了Tau在体外和体内传播.

结论:

开发的hiPSC衍生神经元模型为研究4R病提供了强大的平台.
在神经退行性疾病中,UFMylation级联是一种有前途的治疗标.

关键词:

在CRISPRi屏幕上没有基化细胞内分泌物人类神经元其他国家神经退行症神经元活动复原体病症

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