大规模的RNA-Seq挖掘揭示了环氧胺诱导TDP-43密码前子
Irika R Sinha1,2, Parker S Sandal2, Holly Spence3
1Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Nature communications
|July 27, 2025
概括
核清除和TDP-43蛋白的聚合是神经退行性疾病的标志. 我们发现,环氧胺触发了TDP-43密码外子的包含,揭示了重金属毒性和神经退行过程中的氧化应激的潜在联系.
科学领域:
- 神经生物学 神经生物学 神经生物学
- 基因组学就是基因组学.
- 药物发现 药物发现 药物发现
背景情况:
- TDP-43蛋白病理学是肌缩性侧面硬化,前性痴呆 (ALS-FTD) 和其他神经退行性疾病的核心.
- TDP-43的功能丧失导致了神秘的外因子包容,这是一个在生物流体和脑组织中可检测的生物标志物.
- 驱动TDP-43失调的上游机制尚未完全理解.
研究的目的:
- 开发一个资源来量化TDP-43密码外子包含在公共RNA测序数据中的含量.
- 在各种人类细胞和组织中建立基线隐秘的外子包容水平.
- 识别影响TDP-43病理的新型治疗剂或环境因素.
主要方法:
- 开发了SnapMine,这是一个基于Web的工具,用于分析TDP-43密码外子包含在大规模RNA测序数据集中的分析.
- 在不同的人类细胞和组织类型中量化密码的外显子纳入.
- 对影响TDP-43密码外型子包容性的化合物的非相关RNA测序研究进行了选.
主要成果:
- 在各种人体细胞和组织中为TDP-43隐秘外子体的包含建立了参考水平.
- 鉴定了一种抗真菌药物 - - 环氧胺 (CPX),作为一种强大的诱导TDP-43密码外子在老鼠和人类细胞中的包含.
- 证明CPX诱导的隐秘外子体含有与重金属毒性和氧化应激有关.
结论:
- 公共RNA测序档案是发现疾病机制的不足资源.
- 重金属毒性和氧化应激可能导致神经退行症中TDP-43失调.
- 由CPX诱导的密码性外基子含入为研究TDP-43相关病理提供了一种新型模型.
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