活化成纤维细胞生长因子受体1减轻多聚pr诱导的氧化应激和蛋白质翻译损伤。

IF 1.7 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Taisei Ito, Kazuki Ohuchi, Hisaka Kurita, Takanori Murakami, Shinnosuke Takizawa, Ayaka Fujimaki, Junya Murata, Yasuhisa Oida, Isao Hozumi, Kiyoyuki Kitaichi, Masatoshi Inden
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引用次数: 0

摘要

肌萎缩侧索硬化症(ALS)是一种以选择性运动神经元细胞死亡为特征的神经退行性疾病。9号染色体开放阅读框72 (C9orf72)基因中的GGGGCC六核苷酸重复扩增(HRE)是ALS的主要致病因素。这种异常的HRE触发五种类型的二肽重复蛋白(DPR),每一种由两个交替的氨基酸表达组成。在dpr中,富含精氨酸的Poly-PR主要定位于细胞核,对运动神经元和皮质神经元具有特别强的毒性。关于多pr诱导的神经毒性,已经提出了几种机制。在本研究中,表达poly- pr的NSC34运动神经元样细胞表现出氧化应激的增加。已知成纤维细胞生长因子受体1 (FGFR1)促进神经发生并抑制神经元凋亡。然而,其对dpr诱导的毒性的神经保护作用尚未见报道。在这里,我们证明了FGFR1激活通过上调核因子红细胞2相关因子2 (NRF2)的表达来降低氧化应激。此外,我们提出通过FGFR1激活NRF2的增加可能是由于蛋白质翻译损伤的减轻。总的来说,这些发现表明,FGFR1激活可提供抗多pr毒性的神经保护,并可能代表ALS的潜在治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Activated Fibroblast Growth Factor Receptor 1 Mitigated Poly-PR-Induced Oxidative Stress and Protein Translational Impairment.

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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来源期刊
CiteScore
3.50
自引率
5.00%
发文量
247
审稿时长
2 months
期刊介绍: Biological and Pharmaceutical Bulletin (Biol. Pharm. Bull.) began publication in 1978 as the Journal of Pharmacobio-Dynamics. It covers various biological topics in the pharmaceutical and health sciences. A fourth Society journal, the Journal of Health Science, was merged with Biol. Pharm. Bull. in 2012. The main aim of the Society’s journals is to advance the pharmaceutical sciences with research reports, information exchange, and high-quality discussion. The average review time for articles submitted to the journals is around one month for first decision. The complete texts of all of the Society’s journals can be freely accessed through J-STAGE. The Society’s editorial committee hopes that the content of its journals will be useful to your research, and also invites you to submit your own work to the journals.
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