翻译后修改 控制 Tau 的相位过渡
Wyatt C Powell1, McKinley Nahum1, Karl Pankratz1
1Department of Chemistry, University of Colorado, Boulder, Colorado 80309, United States.
bioRxiv : the preprint server for biology
|April 1, 2024
概括
在阿尔茨海默病 (AD) 模型中,TAU蛋白的翻译后修饰 (PTM) 通常会阻碍对联螺旋丝 (PHF) 的形成. 这些修饰,特别是酸化,在调节聚和液态液相分离 (LLPS) 中起着至关重要的作用.
科学领域:
- 神经科学是一个神经科学.
- 生物化学 生物化学
- 分子生物学分子生物学
背景情况:
- 在阿尔茨海默氏症 (AD) 大脑中,tau蛋白自组合成配对螺旋丝 (PHF).
- 在PHF形成中,AD特异性后翻译修饰 (PTMs) 的作用尚不清楚.
- 了解PTM对于阐明神经退行性疾病中的Tau病理至关重要.
研究的目的:
- 为了研究AD特异性PTMs对Tau的影响{291-391) 自组装到PHF中.
- 分析N-乙化,酸化和N-糖化对Tau聚合动学的影响.
- 在各种条件下探索PTMs对Tau的液态-液态相分离 (LLPS) 的影响.
主要方法:
- 的合成生产 ((291-391) 用AD特异性的PTM (N-乙氨酸,素,酸氨酸,N-糖化).
- 传输电子显微镜 (TEM) 和冷电子显微镜 (cryo-EM) 用于结构分析.
- 光学显微镜技术用于研究体外组合,肝素诱导聚合和RNA介导的LLPS.
主要成果:
- 特别针对AD的PTM通常在实验室中抑制了TAU组装到PHF中.
- 酸化始终缓解了Tau聚合和LLPS,而乙化的影响是可变的,取决于地点.
- 发现纤维细胞核外的PTM在PHF核形成中起着关键作用,大多数PTM在肝素诱导模型中减缓聚合.
结论:
- 特定地点的PTM和环境因素复杂地调节Tau聚合动力学.
- PTMs,特别是那些位于有序丝芯之外的PTMs,是TAU自组装到PHF结构的关键调节者.
- 这些发现增强了对阿尔茨海默病中陶氏病理学的分子基础的理解.
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