Neurons derived from human induced pluripotent stem cells (hIPSCs) hold great potential for unravelling the pathological mechanisms underlying neurological diseases. However, when it comes to tauopathies, hIPSC models are limited by their low expression of 4R tau and difficulty in reproducing the characteristic pathological tau protein inclusions. In a study published in Cell, Parra Bravo, Giani et al. used CRISPR–Cas9 gene editing to express 4R tau carrying the highly aggregate-prone MAPT P301S mutation in hIPSC-derived neurons (4R-P301S). Upon seeding with tau fibrils, these 4R-P301S neurons showed robust tau aggregation and propagation. Neurons harboring tau inclusions displayed reduced firing activity and evidence of endolysosomal dysfunction, in keeping with tauopathy phenotypes. Applying a CRISPRi screen to their new hIPSC models, the authors identified potential modifiers of tau propagation, including genes involved in UFMylation. Disrupting the UFMylation cascade reduced the spread of tau inclusions both in the 4R-P301S hIPSC-derived neurons and in an in vivo mouse model. These newly engineered hIPSC lines could be used to investigate other aspects of tau pathology, such as the mechanisms of tau propagation across cells or how different tau strains give rise to different tauopathies.

Original reference: Cell https://doi.org/10.1016/j.cell.2024.03.015 (2024)

源自人类诱导多能干细胞（hIPSC）的神经元在揭示神经系统疾病的病理机制方面具有巨大的潜力。然而，当涉及 tau 病时，hIPSC 模型因其 4R tau 表达低且难以再现特征性病理性 tau 蛋白内含物而受到限制。Parra Bravo、Giani 等人在《Cell》杂志上发表的一项研究中。使用 CRISPR-Cas9 基因编辑在 hIPSC 衍生的神经元中表达携带高度聚集倾向的 MAPT P301S 突变的 4R tau (4R-P301S)。在接种 tau 原纤维后，这些 4R-P301S 神经元表现出强大的 tau 聚集和传播。含有 tau 蛋白包涵体的神经元表现出放电活动减少和内溶酶体功能障碍的证据，与 tau 蛋白病表型一致。作者将 CRISPRi 筛选应用于他们的新 hIPSC 模型，发现了 tau 传播的潜在修饰因子，包括参与 UFMylation 的基因。破坏 UFMylation 级联可减少 4R-P301S hIPSC 衍生神经元和体内小鼠模型中 tau 包含物的扩散。这些新设计的 hIPSC 系可用于研究 tau 病理学的其他方面，例如 tau 跨细胞传播的机制或不同的 tau 菌株如何引起不同的 tau 病。

原文参考： Cell https://doi.org/10.1016/j.cell.2024.03.015 (2024)