Activated Fibroblast Growth Factor Receptor 1 Mitigated Poly-PR–Induced Oxidative Stress and Protein Translational Impairment

Taisei Ito; Kazuki Ohuchi; Hisaka Kurita; Takanori Murakami; Shinnosuke Takizawa; Ayaka Fujimaki; Junya Murata; Yasuhisa Oida; Isao Hozumi; Kiyoyuki Kitaichi; Masatoshi Inden

doi:10.1248/bpb.b24-00794

Regular Article

Activated Fibroblast Growth Factor Receptor 1 Mitigated Poly-PR–Induced Oxidative Stress and Protein Translational Impairment

Taisei Ito, Kazuki Ohuchi, Hisaka Kurita, Takanori Murakami, Shinnosuke Takizawa, Ayaka Fujimaki, Junya Murata, Yasuhisa Oida, Isao Hozumi, Kiyoyuki Kitaichi, Masatoshi Inden

Author information

Taisei Ito
Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, 1–25–4 Daigaku-nishi, Gifu 501–1196, Japan
Laboratory of Pharmaceutics, Gifu Pharmaceutical University, 1–25–4 Daigaku-nishi, Gifu 501–1196, Japan
Kazuki Ohuchi
Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, 1–25–4 Daigaku-nishi, Gifu 501–1196, Japan
Hisaka Kurita
Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, 1–25–4 Daigaku-nishi, Gifu 501–1196, Japan
Takanori Murakami
Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, 1–25–4 Daigaku-nishi, Gifu 501–1196, Japan
Shinnosuke Takizawa
Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, 1–25–4 Daigaku-nishi, Gifu 501–1196, Japan
Ayaka Fujimaki
Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, 1–25–4 Daigaku-nishi, Gifu 501–1196, Japan
Junya Murata
Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, 1–25–4 Daigaku-nishi, Gifu 501–1196, Japan
Yasuhisa Oida
Laboratory of Pharmaceutics, Gifu Pharmaceutical University, 1–25–4 Daigaku-nishi, Gifu 501–1196, Japan
Isao Hozumi
Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, 1–25–4 Daigaku-nishi, Gifu 501–1196, Japan
Kiyoyuki Kitaichi
Laboratory of Pharmaceutics, Gifu Pharmaceutical University, 1–25–4 Daigaku-nishi, Gifu 501–1196, Japan
Masatoshi Inden Corresponding author
Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, 1–25–4 Daigaku-nishi, Gifu 501–1196, Japan

Keywords: amyotrophic lateral sclerosis, chromosome 9 open reading frame 72, proline (P)–arginine (R) DPR (poly-PR), fibroblast growth factor receptor 1, oxidative stress, nuclear factor erythroid 2-related factor 2

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Supplementary material

2025 Volume 48 Issue 2 Pages 93-100

DOI https://doi.org/10.1248/bpb.b24-00794

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Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective motor neuron cell death. A GGGGCC hexanucleotide repeat expansion (HRE) within the chromosome 9 open reading frame 72 (C9orf72) gene is a major causative factor in ALS. This abnormal HRE triggers five types of dipeptide repeat protein (DPR), each composed of two alternating amino acid expressions. Among the DPRs, arginine-rich Poly-PR localizes predominantly to the nucleus, exerting particularly strong toxicity on motor and cortical neurons. Several mechanisms have been proposed for poly-PR–induced neurotoxicity. In this study, poly-PR–expressing NSC34 motor neuron-like cells showed an increase in oxidative stress. Fibroblast growth factor receptor 1 (FGFR1) is known to promote neurogenesis and inhibit apoptosis in neurons. However, its neuroprotective effects against DPR-induced toxicity have not been previously reported. Here, we demonstrated that FGFR1 activation reduced oxidative stress by upregulating nuclear factor erythroid 2-related factor 2 (NRF2) expression. Furthermore, we propose that the increase in NRF2 through FGFR1 activation may result from the alleviation of protein translation impairment. Overall, these findings suggest that FGFR1 activation provides neuroprotection against poly-PR toxicity and may represent a potential therapeutic strategy for ALS.

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