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压力颗粒内部的TDP-43的内凝解产生病态聚合物

Xiao Yan¹, David Kuster¹, Priyesh Mohanty²

¹Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Dresden 01307, Saxony, Germany.

|May 24, 2025

概括

在神经退行性疾病中,TAR DNA 结合蛋白 43 (TDP-43) 的细胞聚合需要在压力颗粒和氧化压力中度. 这些因素触发了凝结体内脱,导致了病态的TDP-43聚合物.

科学领域:

神经生物学
分子生物学
生物化学

背景情况:

核蛋白TARDNA结合蛋白43 (TDP-43) 的细胞聚合与神经退行性疾病有关.
对于TDP-43聚合的确切触发因素仍在调查中.

研究的目的:

阐明启动TDP-43聚合的关键事件.
研究压力颗粒和氧化应激在TDP-43病理中的作用.

主要方法:

使用诱导多能干细胞衍生的运动神经元 (iPS运动神经元).
检查了一种疾病的小鼠模型和人类患者样本.
设计TDP-43变种来评估聚合机制.

主要成果:

TDP-43聚合需要在应力颗粒和并发性氧化应力中的高度.
这些条件诱导了凝结体内脱,形成了动态的TDP-43富含相,成熟为聚合物.
在iPS运动神经元,小鼠模型和患者样本中观察到聚合物.
机制包括RRM1域展开的二硫化键和C端的疏水相互作用.
设计的TDP-43变种可以防止聚合物形成.

结论:

TDP-43聚合是一种两步过程,涉及度和氧化应激诱导的凝结体内脱.
这种由特定蛋白质域相互作用驱动的脱机制对于病态聚合物形成至关重要.
这些发现表明神经退行性疾病中蛋白质聚合的通用途径.

关键词:

美国一个FTD 一个TDP-43 生物分子凝结物在冷凝液内进行脱神经退行性疾病氧化应激阶段分离蛋白质聚合物压力颗粒

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