Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Biomedical Chemistry, School of International Health, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8654, Japan.
Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Stem Cell Reports. 2019 Oct 8;13(4):684-699. doi: 10.1016/j.stemcr.2019.08.011. Epub 2019 Sep 19.
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.
已知微管相关蛋白 tau（MAPT）基因突变可导致家族性额颞叶痴呆（FTD）。R406Wtau 突变是一种独特的错义突变，其患者表现出阿尔茨海默病（AD）样表型，而不是更典型的 FTD 表型。在这项研究中，我们建立了患者来源的诱导多能干细胞（iPSC）模型，以研究 R406W 突变引起的疾病病理。我们从患者中生成 iPSCs，并使用 CRISPR/Cas9 建立同基因系。将 iPSCs 诱导为大脑类器官，然后将其解离为具有高纯度的皮质神经元。在这种神经元培养物中，突变型 tau 蛋白的磷酸化水平降低，并且被钙蛋白酶逐渐碎片化。此外，突变型 tau 蛋白发生定位错误，并且患者来源的神经元的轴突显示出形态和功能异常，这些异常可通过微管稳定来挽救。我们的研究结果为 tau 病理提供了机制上的见解，并为治疗干预提供了潜力。
