Pathological Progression Induced by the Frontotemporal Dementia-Associated R406W Tau Mutation in Patient-Derived iPSCs
| Autor: | Sumihiro Maeda, Shin-ichi Hisanaga, Hirotaka Watanabe, Akihiko Takashima, Takeshi Ikeuchi, Naruhiko Sahara, Celeste M. Karch, Mutsuki Amano, Hideyuki Okano, Taeko Kimura, Sho Yoshimatsu, Mari Nakamura, Fumihiko Kisa, Kozo Kaibuchi, Tomohiro Miyasaka, Seiji Shiozawa, Daisuke Tsuboi |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Tau protein Mutant Induced Pluripotent Stem Cells tau Proteins Biology medicine.disease_cause Biochemistry Article 03 medical and health sciences 0302 clinical medicine neurodegenerative disease mental disorders disease modeling Genetics medicine Missense mutation Humans tau Phosphorylation Induced pluripotent stem cell Alleles Neurons Mutation iPSC Calpain Phosphotransferases FTD Cell Biology medicine.disease Phenotype 3. Good health Mitochondria 030104 developmental biology Amino Acid Substitution Frontotemporal Dementia biology.protein Cancer research Disease Progression Disease Susceptibility 030217 neurology & neurosurgery Developmental Biology Frontotemporal dementia |
| Zdroj: | Stem Cell Reports |
| ISSN: | 2213-6711 |
| Popis: | Summary 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. Graphical Abstract Highlights • Phenotype analysis of FTD R406W mutant tau using iPSC-derived neurons • Homogeneous neuronal population obtained via dissociation of cerebral organoids • Altered phosphorylation and fragmentation state of R406W mutant tau • Multiple axonal defects in patient neurons rescued with microtubule stabilization In this article, Nakamura and colleagues establish an iPSC-derived neuronal model from frontotemporal dementia patients with the tau R406W mutation and gain insight into the disease pathology. Here, the R406W mutant tau exhibited reduced phosphorylation levels and was prone to fragmentation by calpain. Furthermore, the patients’ neurons displayed multiple axonal defects caused by microtubule destabilization. |
| Databáze: | OpenAIRE |
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