Pathological Progression Induced by the Frontotemporal Dementia-Associated R406W Tau Mutation in Patient-Derived iPSCs
Pathological Progression Induced by the Frontotemporal Dementia-Associated R406W Tau Mutation in Patient-Derived iPSCs
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DOI：
10.1016/j.stemcr.2019.08.011
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发表时间：
2019-10-08
影响因子：
5.9
通讯作者：
Okano, Hideyuki
中科院分区：
文献类型：
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作者：
Nakamura, Mari;Shiozawa, Seiji;Okano, Hideyuki
已知微管相关蛋白 tau (MAPT) 基因突变会导致家族性额颞叶痴呆 (FTD)。 R406W tau 突变是一种独特的错义突变，据报道其患者表现出类似阿尔茨海默病 (AD) 的表型，而不是更典型的 FTD 表型。在本研究中，我们建立了源自患者的诱导多能干细胞（iPSC）模型，以研究 R406W 突变诱导的疾病病理。我们从患者身上生成 iPSC，并使用 CRISPR/Cas9 建立等基因系。 iPSC 被诱导形成大脑类器官，并解离成高纯度的皮质神经元。在这种神经元培养物中，突变 tau 蛋白表现出磷酸化水平降低，并且越来越多地被钙蛋白酶裂解。此外，突变的 tau 蛋白定位错误，患者来源的神经元的轴突表现出形态和功能异常，但微管稳定化可以挽救这些异常。我们的研究结果提供了对 tau 病理学的机制见解以及治疗干预的潜力。
Mutations in the microtubule-associated protein tau (MAPT) gene are known to cause familial frontotemporal dementia (FTD). The R406W tau mutation is a unique missense mutation whose patients have been reported to exhibit Alzheimer's disease (AD)-like phenotypes rather than the more typical FTD phenotypes. In this study, we established patient-derived induced pluripotent stem cell (iPSC) models to investigate the disease pathology induced by the R406W mutation. We generated iPSCs from patients and established isogenic lines using CRISPR/Cas9. The iPSCs were induced into cerebral organoids, which were dissociated into cortical neurons with high purity. In this neuronal culture, the mutant tau protein exhibited reduced phosphorylation levels and was increasingly fragmented by calpain. Furthermore, the mutant tau protein was mislocalized and the axons of the patient-derived neurons displayed morphological and functional abnormalities, which were rescued by microtubule stabilization. The findings of our study provide mechanistic insight into tau pathology and a potential for therapeutic intervention.