TDP-43的单质化是诱导TDP-43病理的关键决定因素,在肌缩性侧面硬化症中
Kotaro Oiwa1,2, Seiji Watanabe1,3, Kazunari Onodera2,4,5
1Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi 464-8601, Japan.
Science advances
|August 4, 2023
概括
损伤的TAR DNA结合蛋白-43 (TDP-43) 分解导致其细胞质错位和聚合,这是肌缩侧面硬化症 (ALS) 的关键病理. 这种TDP-43单化是ALS病理学的关键驱动因素.
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 遗传学 是一个
背景情况:
- TAR DNA 结合蛋白-43 (TDP-43) 的细胞质聚合定义了肌缩性侧面硬化症 (ALS) 的病理.
- 在ALS中导致TDP-43错位和聚合的确切机制仍然不完全理解.
研究的目的:
- 调查TDP-43二分化在肌缩侧面硬化症的发病过程中的作用.
- 确定ALS中TDP-43病理之前的关键分子事件.
主要方法:
- 从零星ALS患者中对死后的大脑和脊髓组织的分析.
- 野生类型和突变TDP-43在细胞培养 (Neuro2a) 和诱导多能干细胞衍生的运动神经元中的表达.
- 使用TDP-DiLuc双分子发光补充试验实时监测TDP-43的二分化.
主要成果:
- 在ALS患者的组织中,TDP-43的二元化/多元化受损.
- 缺少N端二元化的TDP-43形成了病态包容体,并在运动神经元中表现出Nxf1依赖的细胞质错位.
- 表现为二元化缺陷的TDP-43概述了类似于ALS的病理,包括聚合物形成和播种效应.
- 减少的TDP-43 N端二分化在与异常RNA代谢相关的转录抑制模型的病理变化之前发生.
结论:
- 损坏的TDP-43二分化是诱导ALS中TDP-43病理的一个关键决定因素.
- TDP-43单化是驱动细胞质错位和聚合在肌缩侧面硬化症的一个关键事件.
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