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压力颗粒中的蛋白相互作用的环境依赖性和疾病特异性多样性
Sebastian Markmiller1, Sahar Soltanieh2, Kari L Server1
1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Stem Cell Program, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92039, USA.
Cell
|January 27, 2018
概括
分析了与神经退行相关的压力颗粒 (SG),以确定新的成分. 在ALS患者细胞中发现异常的SG行为,
科学领域:
- 细胞生物学
- 神经科学
- 生物化学
背景情况:
- 应激颗粒 (SG) 是细胞应激过程中形成的动态RNP聚合物.
- 人类神经退行性疾病的机制越来越多地涉及SG.
研究的目的:
- 在细胞类型和神经退行性环境中全面识别人类SG蛋白质和组成多样性.
- 调查SG蛋白相互作用在SG形成和动态中的作用.
- 在肌缩侧面硬化症 (ALS) 中探索SG变化,并确定体内神经毒性修饰因子.
主要方法:
- 使用酸盐过氧化酶 (APEX) 接近性标记与质谱学相结合.
- 使用免疫光用于蛋白质定位和SG特征.
- 在患者衍生细胞和ALS/FTD的Drosophila模型中研究了SG动力学和组成.
主要成果:
- 确定了大约150个新的人类SG成分,扩展已知的SG蛋白质组.
- 揭示了先前存在的蛋白质相互作用网络,促进了快速的SG凝聚.
- 显示压力和细胞类型依赖的SG多样性,神经元SG表现出独特的复杂性.
- 在ALS患者细胞中观察到异常的SG动态,组成和分布.
- 在Drosophila模型中确定了与SG相关的神经毒性修饰剂.
结论:
- SG蛋白质对于理解神经退行症至关重要.
- 这些发现为针对神经退行性疾病的治疗策略提供了基础.
- 在神经退行性病理中,SG的组成和动态是关键因素.
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