压力诱导的TDP-43核凝结导致拼接功能丧失和STMN2耗尽
Wan-Ping Huang1, Brittany C S Ellis1, Rachel E Hodgson1
1Sheffield Institute for Translational Neuroscience and Neuroscience Institute, University of Sheffield, Sheffield, UK.
Cell reports
|June 28, 2024
概括
压力导致TDP-43蛋白形成核凝聚物,损害其在拼接中的功能,特别是对于神经退行性疾病研究中至关重要的STMN2RNA.
科学领域:
- 神经生物学 神经生物学 神经生物学
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
背景情况:
- TDP-43蛋白质失调与神经退行性疾病有关.
- 外在的压力因素可以作为一个
- 第二次击中.
- 在疾病的发病过程中.
- 在应力细胞中,TDP-43经历可逆的核凝结.
研究的目的:
- 为了研究应力诱导性TDP-43核冷凝的性质.
- 确定TDP-43凝结在细胞功能和神经退行症中的作用.
- 检查ALS相关突变对TDP-43凝结物的影响.
主要方法:
- 同焦纳米扫描试验分析TDP-43凝结.
- 生物化学试验研究TDP-43寡合化,ATP依赖性和RNA相互作用.
- 拼接变化和蛋白质耗尽的分析,专注于STMN2RNA和蛋白质.
主要成果:
- 应力诱导型TDP-43凝聚物是缺少RNA的非液体组件,需要TDP-43的寡合化和ATP.
- RNA抑制了这些凝结物的形成.
- 与ALS相关的突变通过影响其与核糖蛋白组合的亲和力来改变压力诱导的TDP-43凝结.
- 核凝结暂时使TDP-43失活,导致蛋白质相互作用的丧失和拼接受损,特别是影响STMN2RNA和蛋白质水平.
结论:
- 压力诱导的核TDP-43凝结代表了神经退行症的早期病理事件.
- 这些凝结物导致功能缺陷,包括改变拼接.
- 调节细胞应激反应可能为ALS提供治疗策略.
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