乌比基特异性化酶-19将TDP-43聚合与ER压力联系起来
Yan Yan1, Xinming Wang1, Hanna Jeon1
1Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106.
概括
乌比基因特异性酶-19 (USP19) 双双基因化TARDNA结合蛋白43 (TDP-43),促进其聚合和内质网膜应激在神经退行性疾病,如ALS和FTLD-TDP.
科学领域:
- 神经生物学 神经生物学 神经生物学
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
背景情况:
- TDP-43聚合是ALS和FTLD-TDP病原体的核心.
- 在TDP-43蛋白质稳定中deubiquitinases (DUBs) 的作用在很大程度上是未知的.
- 乌比基因化调节TDP-43的清除,但DUB的影响还没有得到充分研究.
研究的目的:
- 为了识别控制TDP-43蛋白质稳定性的DUBs.
- 研究USP19在TDP-43聚合和相关病理中的功能.
- 探索USP19在ER压力中的作用及其在ALS/FTLD-TDP中的治疗潜力.
主要方法:
- 没有偏见的DUB选.
- 在体外和体内生物化学测定.
- 对人类FTLD-TDP脑组织的分析.
- 在小鼠模型 (TAR4小鼠) 中进行基因操纵.
主要成果:
- USP19被确定为TDP-43导向的DUB,可以去除K48/K63的无处不在链.
- USP19促进了TDP-43的C端片段 (TDP-CTF) 聚合,特别是ER定异型 (USP19-ER).
- USP19将TDP-CTF聚合与ER压力联系起来,其水平在FTLD-TDP大脑中升高.
- 在小鼠模型中,USP19的遗传减少改善了TDP-43病理,ER压力和运动缺陷.
结论:
- USP19是TDP-43蛋白质稳定和聚合的关键调节剂.
- USP19通过促进聚合和ER压力,加剧了TDP-43相关的神经退行.
- USP19代表了ALS和FTLD-TDP的潜在治疗目标.
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