氨-tRNA氨基化受ALS/FTD相关的C9orf72 C4G2重复RNA影响
Mirjana Malnar Črnigoj1,2, Urša Čerček1,2, Xiaoke Yin3
1Department of Biotechnology, Jožef Stefan Institute, Ljubljana, 1000, Slovenia.
Nature communications
|September 16, 2023
概括
这种C9orf72突变通过抑制氨酸-tRNA合成酶 (FARSA) 来破坏蛋白质合成. 这导致氨的吸收减少,并导致神经退行性疾病,如ALS和FTD.
科学领域:
- 神经科学是一个神经科学.
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
背景情况:
- C9orf72基因的六核酸重复扩张是肌缩侧面硬化症 (ALS) 和前性痴呆症 (FTD) 的主要遗传原因.
- 一个拟议的疾病机制涉及重复的转录干扰RNA结合蛋白,导致细胞功能障碍.
研究的目的:
- 为了识别细胞内C9orf72反意义重复RNA的相互作用体.
- 研究这种相互作用对蛋白质合成的功能后果.
主要方法:
- 鉴定氨酸-tRNA合成酶 (FARS) 亚单元α (FARSA) 作为CCCCCGG反感重复RNA的关键相互作用体.
- 评估反感性RNA对tRNAPhe氨基基化对FARS.的影响.
- 在细胞模型和患者组织中分析全球蛋白质合成和富含 fenylalanine 蛋白质的表达.
主要成果:
- 反感重复RNA直接抑制了FARSA的氨基化活性.
- 这种抑制导致充电tRNAPhe的水平降低.
- 在细胞模型和患者组织中观察到,氨酸融入蛋白质的总体减少和富含氨酸的蛋白质的表达减少.
结论:
- 这项研究揭示了FARSA的功能性抑制通过反感C9orf72重复RNA.
- 损坏的tRNA氨基化有助于蛋白质合成缺陷.
- 这种机制为C9orf72相关的ALS和FTD的分子病理提供了新的见解.
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