DBT是一种代谢开关,用于在蛋白质体损伤下维持蛋白质稳定性
Ran-Der Hwang1,2, YuNing Lu1,2, Qing Tang1,2
1Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Baltimore, United States.
eLife
|September 10, 2024
概括
失去了二利胺分支链晶酶E2 (DBT) 通过增强蛋白质清除和激活自来防止蛋白质毒性. 这一发现对像ALS这样的神经退行性疾病有影响.
科学领域:
- 细胞生物学 细胞生物学
- 神经科学是一个神经科学.
- 代谢调节 代谢调节 代谢调节
背景情况:
- 蛋白质毒性压力导致神经退行,包括肌缩性侧面硬化症 (ALS).
- 细胞蛋白质质量控制依赖于蛋白质体和自体降解途径.
- 识别蛋白质毒性的调节者对于理解疾病的发病过程至关重要.
研究的目的:
- 通过蛋白质酶抑制诱导的细胞毒性新型调节剂的识别.
- 调查二利胺分支链晶酶E2 (DBT) 在细胞蛋白质稳定和神经退行中的作用.
主要方法:
- 全基因组的CRISPR屏幕用于识别影响蛋白酶体抑制诱导细胞死亡的基因.
- 对蛋白质清除,自激活和在DBT损失后的代谢变化进行分析.
- 在体内研究使用*Drosophila*和具有ALS相关突变的哺乳动物神经元.
主要成果:
- 丢失的DBT显著地防止蛋白质酶抑制诱导的细胞死亡.
- 缺少DBT促进了ubiquitinated蛋白质的清除,并通过AMP激活蛋白激酶 (AMPK) 激活了自.
- 在神经元模型中,丢失DBT可以防止ALS相关突变TDP-43的蛋白质毒性.
结论:
- DBT作为细胞对蛋白质毒性压力的反应的关键调节者.
- 在ALS患者的组织中,DBT是上调调节的,这表明它与疾病有关.
- 针对DBT可能为特征为蛋白质聚合的神经退行性疾病提供治疗策略.
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