若年性認知症を来す前頭側頭葉変性症に対する治療薬候補と治療標的分子のiPS創薬による同定

2024-04-04 京都大学iPS細胞研究所

<関連情報>

• https://www.cira.kyoto-u.ac.jp/j/pressrelease/news/250404-150000.html
• https://www.sciencedirect.com/science/article/pii/S0171933525000093

iPSCスクリーニングにより、FTLD-タウの治療標的となりうるCACNA2D2が同定された iPSC screening identifies CACNA2D2 as a potential therapeutic target for FTLD-Tau

Keiko Imamura, Ayako Nagahashi, Aya Okusa, Tomoki Sakasai, Kayoko Tsukita, Yumiko Kutoku, Yutaka Ohsawa, Yoshihide Sunada, Naruhiko Sahara, Nicholas M. Kanaan, Makoto Higuchi, Kohji Moriⁱ, Manabu Ikedaⁱ, Haruhisa Inoue
European Journal of Cell Biology  Available online: 21 March 2025
DOI:https://doi.org/10.1016/j.ejcb.2025.151484

Highlights

• Compound screening was conducted to find treatments for FTLD-tau using patient iPSCs.
• Gabapentinoids reduced neuronal death and tau oligomer accumulation in FTLD-tau neurons.
• A knockout approach showed that α2δ-2 was a potential molecular target for FTLD-tau therapy.
• Cerebral organoids exhibited neurodegenerative features associated with α2δ-2.

Abstract

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.