@article{4c897f5ee9e6449f9bdebdd85fe8fe41,
title = "Pathological Progression Induced by the Frontotemporal Dementia-Associated R406W Tau Mutation in Patient-Derived iPSCs",
abstract = "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.",
keywords = "FTD, disease modeling, iPSC, neurodegenerative disease, tau",
author = "Mari Nakamura and Seiji Shiozawa and Daisuke Tsuboi and Mutsuki Amano and Hirotaka Watanabe and Sumihiro Maeda and Taeko Kimura and Sho Yoshimatsu and Fumihiko Kisa and Karch, {Celeste M.} and Tomohiro Miyasaka and Akihiko Takashima and Naruhiko Sahara and Hisanaga, {Shin ichi} and Takeshi Ikeuchi and Kozo Kaibuchi and Hideyuki Okano",
note = "Funding Information: We would like to thank Drs. T. Sone and M. Ishikawa for providing technical assistance and all members of the H.O. laboratory for their generous support. We are also thankful to Dr. S. Yamanaka (Kyoto University) for providing us with the 201B7 iPSC line and Drs. T. Tomiyama and T. Umeda (Osaka City University) for providing us with the Mito-eYFP construct. This study was supported by the Acceleration Program for Intractable Disease Research Utilizing Disease-specific iPS Cells from the Japan Agency for Medical Research and Development (grant no. 19bm0804003h0003 ) and by the Scientific Research in Innovative Areas “Brain Protein Aging and Dementia Control” from the MEXT to H.O. The generation of the iPSC lines (patient #3) was supported by grants from the National Institutes of Health ( K01 AG046374 and P50 AG005681 ). H.O. is a founding scientist of K Pharma and SanBio. The authors declare no competing interests. Funding Information: We would like to thank Drs. T. Sone and M. Ishikawa for providing technical assistance and all members of the H.O. laboratory for their generous support. We are also thankful to Dr. S. Yamanaka (Kyoto University) for providing us with the 201B7 iPSC line and Drs. T. Tomiyama and T. Umeda (Osaka City University) for providing us with the Mito-eYFP construct. This study was supported by the Acceleration Program for Intractable Disease Research Utilizing Disease-specific iPS Cells from the Japan Agency for Medical Research and Development (grant no. 19bm0804003h0003) and by the Scientific Research in Innovative Areas ?Brain Protein Aging and Dementia Control? from the MEXT to H.O. The generation of the iPSC lines (patient #3) was supported by grants from the National Institutes of Health (K01 AG046374 and P50 AG005681). H.O. is a founding scientist of K Pharma and SanBio. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = oct,
day = "8",
doi = "10.1016/j.stemcr.2019.08.011",
language = "English",
volume = "13",
pages = "684--699",
journal = "Stem cell reports",
issn = "2213-6711",
publisher = "Cell Press",
number = "4",
}