作为融合在肉瘤中的相分离和聚合的关键调节器的ATP:对肌缩性侧面硬化症病原体的洞察
Keiji Kitamura1, Itta Tsukui2, Fuka Sasaki1
1Graduate School of Pharmacy, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan.
Journal of molecular biology
|June 14, 2025
概括
腺三酸盐 (ATP) 抑制了FUS蛋白的聚合,这是肌缩侧面硬化症 (ALS) 的关键因素. 生理ATP水平保护FUS聚合,这表明在神经退行性疾病中具有治疗作用.
科学领域:
- 生物化学 生物化学
- 神经科学是一个神经科学.
- 分子生物学分子生物学
背景情况:
- 化在肉瘤 (FUS) 是一种RNA结合蛋白,涉及肌缩性侧面硬化症 (ALS) 病原体.
- 异常的液体液相分离 (LLPS) 和FUS的聚合与ALS有关.
- 在调节FUS LLPS和聚合方面,细胞水基的腺三酸盐 (ATP) 的作用尚未完全理解.
研究的目的:
- 研究ATP如何影响野生类型FUS及其与ALS相关的变体的LLPS行为和聚合.
- 阐明ATP调节FUS聚合的分子机制.
- 评估ATP作为ALS治疗剂的潜力.
主要方法:
- 在体外分析研究FUS LLPS和聚合.
- 压力跳跃实验以评估聚合倾向.
- 分子动态模拟以揭示分子相互作用.
- 对FUS变种R495X和P525L的调查.
主要成果:
- ATP使FUS的正常和高压LLPS (HP-LLPS) 不稳定,对HP-LLPS具有更强的抑制作用.
- ATP减少了FUS不可逆转的聚合,特别是在ALS变体中.
- 分子动力学模拟表明ATP的三酸盐和腺素部分破坏了相分离所必需的分子间相互作用.
- 生理ATP度 (1-12mM) 显著抑制了FUS聚合.
结论:
- 细胞内ATP水平降低可能会促进异常的FUS阶段过渡,并导致ALS.
- 通过抑制FUS聚合,ATP起到保护作用.
- 在像ALS这样的神经退行性疾病中,ATP具有作为蛋白相分离和聚合的治疗调节器的潜力.
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