在细胞模型中,C9orf72相关的多-甘氨酸-氨酸通过ERK1/2相互作用促进tau酸化和细胞死亡

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Jiahan Zhuang¹, Zixuan Zhang², Hongfu Jin³

¹Department of Nuclear Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

|October 3, 2025

概括

在前叶退化 (FTLD) 中,C9ORF72 GGGGCC重复扩张通过激活ERK1/2信号来驱动神经元死亡. 这一途径促进病理,建议ERK1/2作为FTLD的治疗点.

科学领域:

神经科学是一个神经科学.
分子生物学分子生物学
遗传学遗传学是一种遗传学.

背景情况:

带有C9ORF72重复扩张的前叶退化 (FTLD) 经常显示同时发生的TDP-43和tau病理.
在C9ORF72突变携带者中,tau病理的严重程度经常加剧.
连接C9ORF72重复扩张与调节失调的机制尚不清楚.

研究的目的:

调查C9ORF72重复扩张和病理之间的机制联系.
探索细胞外调节激酶1/2 (ERK1/2) 信号在C9ORF72相关的病变中的作用.
评估针对ERK1/2信号的治疗潜力.

主要方法:

使用了一个细胞模型,过度表达来自C9ORF72.7的 (GA) 50重复.
研究了 (GA) 50和ERK1/2蛋白之间的相互作用.
评估了 (GA) 50对的酸化和聚合的影响.
研究了使用U0126的ERK1/2抑制对细胞结局的影响.

主要成果:

(GA) 50表达导致显著的神经元细胞死亡.
(GA) 50直接结合并诱导ERK1/2.2的高酸化.
激活ERK1/2信号与增加的陶酸化和聚合相关.
抑制ERK1/2活性显著改善tau病理和细胞死亡.

结论:

(GA) 50诱导的ERK1/2过酸化是C9ORF72相关的FTLD中tau病理的一个关键驱动因素.
ERK1/2信号通路代表了C9ORF72相关的神经退行症的潜在治疗标.
针对聚甘氨氨酸 (GA) 和ERK1/2之间的相互作用,可能会提供一种新的治疗策略.

关键词:

在C9ORF72 ALS/FTLD中.在ERK1/2中.的聚合是tau的聚合.的酸化是的酸化.聚甘氨酸 - 氨酸的组合.

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