聚聚氨胺介导的核糖毒性破坏了亨廷顿病的蛋白质稳定和应激反应
Ranen Aviner1,2,3, Ting-Ting Lee1, Vincent B Masto1
1Department of Biology and Department of Genetics, Stanford University, Stanford, CA, USA.
Nature cell biology
|May 13, 2024
概括
亨廷顿病 (HD) 涉及有毒的亨廷丁 (HTT) 蛋白碎片. 这些碎片是由错误的翻译终止引起的,导致细胞应激和功能障碍,可以通过抑制翻译启动来减轻这种情况.
科学领域:
- 分子生物学分子生物学
- 神经科学是一个神经科学.
- 遗传学 遗传学 是一个
背景情况:
- 亨廷顿病 (HD) 是一种神经退行性疾病,与亨廷丁 (HTT) 基因中扩大的CAG重复有关.
- 连接突变亨廷丁 (mHTT) 聚合与神经毒性的确切机制尚未完全理解.
研究的目的:
- 研究HTT在HD病变发生过程中的翻译和聚合的作用.
- 阐明多重胺 (polyQ) 扩张如何影响HTT转化和蛋白质碎片形成.
- 探索mHTT对翻译延长因子和细胞应激反应的影响.
主要方法:
- 野生型和突变型HTT转换和聚合的分析.
- 在HTT法规中调查上游开放阅读框架的功能.
- 在HD模型 (小鼠和细胞培养) 中评估翻译延长因子eIF5A的水平.
- 评估翻译启动抑制剂对HD细胞模型的影响.
主要成果:
- 在HTT中的PolyQ扩展导致失败的翻译终止,产生截断的,易于聚合的mHTT片段.
- mHTT消耗HD大脑和细胞中的eIF5A,导致核糖体停滞和碰撞.
- 失去eIF5A功能会影响细胞应激恢复和恒温控制.
- 抑制翻译启动减少了早期终止,并减轻了HD模型中的核毒性压力.
结论:
- 错误的翻译终止和随后的eIF5A耗尽是HD病变发生的关键事件.
- 由mHTT引起的核糖体暂停和碰撞有助于神经毒性.
- 定位翻译启动为亨廷顿病提供了潜在的治疗策略.
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