扩大CAG重复RNA的相位过渡和溶酶体降解抑制了全球蛋白质合成
Junmei Lu1,2, Yuyin Pan1, Xinran Feng3
1State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, New Cornerstone Science Laboratory, School of Life Sciences, Fudan University, Shanghai, China.
Autophagy
|October 25, 2023
概括
扩展重复RNA在细胞质中形成固体凝,隔离蛋白质并抑制合成. 这种RNA凝有助于神经退行,突出了神经疾病中的新型致病机制.
科学领域:
- 生物化学 生化学
- 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:
- 生物分子的相位过渡与神经退行性疾病有关.
- 以前的研究重点是蛋白质错折,忽视了像CAG重复RNA凝这样的RNA相过渡.
- 扩展CAG重复RNA (eCAGr RNA) 凝的细胞发生和功能仍然不清楚.
研究的目的:
- 为了研究eCAGrRNA凝的细胞内发生和功能作用.
- 为了确定eCAGrRNA凝的细胞清除机制和分子标.
- 在体内评估eCAGrRNA的致病潜力.
主要方法:
- 细胞成像观察eCAGrRNA凝的形成和定位.
- 生物化学测定用于识别隔离的蛋白质,并评估蛋白质合成率.
- 自和溶酶体通路分析,包括LAMP2C依赖性.
- 在体内小鼠模型表达eCAGrRNA以评估神经生理和行为结果.
主要成果:
- eCAGrRNA在细胞质中形成类似固体的凝,这些凝通过依赖LAMP2C的路径被 lysosomes快速清除.
- 这些细胞质RNA凝将真核延长因子2 (EEF2) 隔离,导致抑制全球蛋白质合成.
- 在体内,单独eCAGrRNA表达在小鼠中诱导了与神经退行相关的电生理学和行为缺陷.
结论:
- 细胞质eCAGrRNA凝是一种新的机制,有助于神经退行.
- 通过RNA凝对EEF2的绑定和随后的蛋白质合成抑制是关键的致病事件.
- 独立于蛋白质表达的eCAGrRNA可以驱动神经退行性表型.
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