iPSC screening identifies CACNA2D2 as a potential therapeutic target for FTLD-Tau
Frontotemporal Lobar Degeneration (FTLD) is a neurodegenerative disorder that affects the frontal and temporal lobes, which are crucial for regulating personality, behavior, and language. Pathologically, FTLD is characterized by Tau protein accumulation and neuronal death. In our effort to identify...
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Elsevier
2025-06-01
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| Series: | European Journal of Cell Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0171933525000093 |
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| author | Keiko Imamura Ayako Nagahashi Aya Okusa Tomoki Sakasai Kayoko Tsukita Yumiko Kutoku Yutaka Ohsawa Yoshihide Sunada Naruhiko Sahara Nicholas M. Kanaan Makoto Higuchi Kohji Mori Manabu Ikeda Haruhisa Inoue |
| author_facet | Keiko Imamura Ayako Nagahashi Aya Okusa Tomoki Sakasai Kayoko Tsukita Yumiko Kutoku Yutaka Ohsawa Yoshihide Sunada Naruhiko Sahara Nicholas M. Kanaan Makoto Higuchi Kohji Mori Manabu Ikeda Haruhisa Inoue |
| author_sort | Keiko Imamura |
| collection | DOAJ |
| description | Frontotemporal Lobar Degeneration (FTLD) is a neurodegenerative disorder that affects the frontal and temporal lobes, which are crucial for regulating personality, behavior, and language. Pathologically, FTLD is characterized by Tau protein accumulation and neuronal death. In our effort to identify disease-modifying treatments, we conducted drug screening using neurons derived from induced pluripotent stem cells (iPSCs) of FTLD-Tau patients. This screening identified gabapentin as an existing drug that suppresses neuronal cell death with suppressed accumulation of Tau oligomers. Treatment with gabapentinoids, including pregabalin and mirogabalin, demonstrated similar neuroprotective effects. These compounds bind to the α2δ subunit of voltage-dependent calcium channels and specifically target the two isoforms α2δ-1 and α2δ-2. To determine which isoform is involved in the neurodegeneration seen in FTLD-Tau, we employed a knockout approach using iPSCs, which revealed that α2δ-2, encoded by CACNA2D2, plays a key role in the degeneration of FTLD-Tau neurons. Moreover, Neural organoids of FTLD-Tau exhibited features indicative of neurodegeneration, and CACNA2D2 knockout reversed a part of the gene expression alterations associated with these neurodegenerative features. These findings suggest that α2δ-2 may be a promising target for disease-modifying therapies in FTLD-Tau. |
| format | Article |
| id | doaj-art-e5b5826638dd4e71a7b3c13b172fb04b |
| institution | OA Journals |
| issn | 0171-9335 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | European Journal of Cell Biology |
| spelling | doaj-art-e5b5826638dd4e71a7b3c13b172fb04b2025-08-20T02:07:38ZengElsevierEuropean Journal of Cell Biology0171-93352025-06-01104215148410.1016/j.ejcb.2025.151484iPSC screening identifies CACNA2D2 as a potential therapeutic target for FTLD-TauKeiko Imamura0Ayako Nagahashi1Aya Okusa2Tomoki Sakasai3Kayoko Tsukita4Yumiko Kutoku5Yutaka Ohsawa6Yoshihide Sunada7Naruhiko Sahara8Nicholas M. Kanaan9Makoto Higuchi10Kohji Mori11Manabu Ikeda12Haruhisa Inoue13Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; iPSC-based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto, Japan; RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, JapanCenter for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, JapanCenter for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, JapanCenter for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, JapanCenter for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; iPSC-based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto, JapanDepartment of Neurology, Kawasaki Medical School, Kurashiki, Okayama, JapanDepartment of Neurology, Kawasaki Medical School, Kurashiki, Okayama, JapanDepartment of Neurology, Kawasaki Medical School, Kurashiki, Okayama, JapanAdvanced Neuroimaging Center, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba, Japan; Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, JapanDepartment of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, United StatesAdvanced Neuroimaging Center, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba, Japan; Neuroetiology and Diagnostic Science, Osaka Metropolitan University Graduate School of Medicine, Osaka, JapanDepartment of Psychiatry, Osaka University Graduate School of Medicine, Suita, JapanDepartment of Psychiatry, Osaka University Graduate School of Medicine, Suita, JapanCenter for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; iPSC-based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto, Japan; RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, Japan; Corresponding author at: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.Frontotemporal Lobar Degeneration (FTLD) is a neurodegenerative disorder that affects the frontal and temporal lobes, which are crucial for regulating personality, behavior, and language. Pathologically, FTLD is characterized by Tau protein accumulation and neuronal death. In our effort to identify disease-modifying treatments, we conducted drug screening using neurons derived from induced pluripotent stem cells (iPSCs) of FTLD-Tau patients. This screening identified gabapentin as an existing drug that suppresses neuronal cell death with suppressed accumulation of Tau oligomers. Treatment with gabapentinoids, including pregabalin and mirogabalin, demonstrated similar neuroprotective effects. These compounds bind to the α2δ subunit of voltage-dependent calcium channels and specifically target the two isoforms α2δ-1 and α2δ-2. To determine which isoform is involved in the neurodegeneration seen in FTLD-Tau, we employed a knockout approach using iPSCs, which revealed that α2δ-2, encoded by CACNA2D2, plays a key role in the degeneration of FTLD-Tau neurons. Moreover, Neural organoids of FTLD-Tau exhibited features indicative of neurodegeneration, and CACNA2D2 knockout reversed a part of the gene expression alterations associated with these neurodegenerative features. These findings suggest that α2δ-2 may be a promising target for disease-modifying therapies in FTLD-Tau.http://www.sciencedirect.com/science/article/pii/S0171933525000093TauFTLDexcitabilitygabapentinoidsiPSCs |
| spellingShingle | Keiko Imamura Ayako Nagahashi Aya Okusa Tomoki Sakasai Kayoko Tsukita Yumiko Kutoku Yutaka Ohsawa Yoshihide Sunada Naruhiko Sahara Nicholas M. Kanaan Makoto Higuchi Kohji Mori Manabu Ikeda Haruhisa Inoue iPSC screening identifies CACNA2D2 as a potential therapeutic target for FTLD-Tau European Journal of Cell Biology Tau FTLD excitability gabapentinoids iPSCs |
| title | iPSC screening identifies CACNA2D2 as a potential therapeutic target for FTLD-Tau |
| title_full | iPSC screening identifies CACNA2D2 as a potential therapeutic target for FTLD-Tau |
| title_fullStr | iPSC screening identifies CACNA2D2 as a potential therapeutic target for FTLD-Tau |
| title_full_unstemmed | iPSC screening identifies CACNA2D2 as a potential therapeutic target for FTLD-Tau |
| title_short | iPSC screening identifies CACNA2D2 as a potential therapeutic target for FTLD-Tau |
| title_sort | ipsc screening identifies cacna2d2 as a potential therapeutic target for ftld tau |
| topic | Tau FTLD excitability gabapentinoids iPSCs |
| url | http://www.sciencedirect.com/science/article/pii/S0171933525000093 |
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