September 20, 2019
Keio University School of Medicine
Japan Agency for Medical Research and Development
A research group led by Professor Hideyuki Okano and Visiting Junior Research Fellow Mari Nakamura of the Department of Physiology, Keio University School of Medicine, and Project Lecturer Seiji Shiozawa of the university's Center for Integrated Medical Research, has elucidated part of the pathological mechanism of familial frontotemporal lobar degeneration (FTLD) by establishing iPS cells from patients and differentiating them into neurons.
This study focused on the R406W mutation (hereafter, tau R406W mutation) in the microtubule-associated protein tau (hereafter, MAPT) gene, one of the causative genes of familial frontotemporal lobar degeneration. This mutation causes symptoms very similar to Alzheimer's disease (dementia).
For comparison, the researchers established a cell line in which the tau R406W gene mutation was corrected to the normal type using genome editing technology, as well as a cell line with the tau R406W mutation on both alleles. Furthermore, they generated brain-like tissues (neurons) called brain organoids from each of these iPS cells and compared them to investigate abnormalities in neurons caused by the tau R406W mutation.
The results showed that neurons derived from iPS cells with the tau R406W mutation exhibited abnormalities in the phosphorylation and localization of the tau protein, as well as degeneration of nerve axons. Furthermore, it was revealed that these phenotypes could be suppressed by a microtubule-stabilizing agent. The tau protein is known to be involved in various neurodegenerative diseases, including Alzheimer's disease, and the mechanism discovered in this study is expected to become a new disease model that will lead to the development of new therapeutic drugs, such as microtubule-stabilizing agents, effective in suppressing these abnormalities.
The results of this research were published in the online edition of "Stem Cell Reports," the official journal of the International Society for Stem Cell Research (ISSCR), on September 19, 2019 (US Eastern Time).
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