老化因子EPS8通过RAC信号过活化诱导与疾病相关的蛋白质聚合
Seda Koyuncu1,2, Yaiza Dominguez-Canterla3,4, Rafael Alis3,4
1Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, Cologne, Germany. skoyunc2@uni-koeln.de.
Nature aging
|September 3, 2025
概括
通过激活EPS8/RAC信号,促进蛋白质聚合,衰老加速神经退行性疾病. 抑制这种途径和USP4可减少聚合和神经退行,为与年龄相关的疾病提供潜在的治疗点.
科学领域:
- 神经科学
- 老龄化研究
- 分子生物学
背景情况:
- 衰老是导致神经退行性疾病的主要危险因素,如亨廷顿病 (HD) 和肌缩侧面硬化症 (ALS).
- 这些疾病的特点是特定蛋白质的病态聚合.
- 分享的晚期发病表明,常见的与衰老相关的机制是各种蛋白质聚合障碍的基础.
研究的目的:
- 研究与衰老相关的信号通路在神经退行性疾病相关的蛋白质聚合中的作用.
- 确定与年龄相关的神经退行症治疗的分子点.
主要方法:
- 使用Caenorhabditis elegans模型研究与年龄相关的EPS8/RAC信号.
- 检查了调节EPS8/RAC信号对与HD相关的多重胺重复和ALS相关的FUS/TDP-43变体的聚合的影响.
- 使用人类细胞模型验证EPS8信号抑制的发现.
- 确定了USP4 (除酶) 作为EPS8降解的调节剂.
主要成果:
- 在虫中,与年龄相关的EPS8/RAC信号过度激活促进了病态蛋白质聚合和神经元功能障碍.
- 在衰老过程中,阻断eps-8或RAC正位器会防止聚合,并保持神经元功能.
- 抑制EPS8信号减少了人体细胞中的蛋白质聚合和神经退行.
- USP4 调节 EPS8 的无处不在和降解;在老化过程中减少 USP4 的上调,减轻 EPS-8 的积累并延长寿命.
结论:
- EPS8/RAC信号传递是与年龄相关的蛋白质聚合和神经退行的主要驱动因素.
- 针对EPS8信号及其调节器USP4,为与年龄相关的神经退行性疾病提供了一个有前途的治疗策略.
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