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Assays for the Degradation of Misfolded Proteins in Cells
Published on: August 28, 2016
一个多重谷氨胺前amyloid寡合物的心肌细胞表达导致心力衰竭
J Scott Pattison1, Atsushi Sanbe, Alina Maloyan
1Department of Pediatrics, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Circulation
|May 21, 2008
概括
在心脏细胞内表达的可溶性甲基胺原 (PAO) 在小鼠中引起毒性和心力衰竭. 这项研究证实PAO足以诱导心脏功能障碍和细胞死亡,突出显示其致病作用.
科学领域:
- 心血管生物学 心血管生物学
- 神经退行性疾病机制 神经退行性疾病机制
- 分子毒理学 分子毒理学
背景情况:
- 可溶性甲基甲酸寡合物 (PAO) 涉及神经毒性,并已在人类心力衰竭样本中观察到.
- 长长的多重氨酸 (PQ) 重复 (>50) 形成PAO,并与诸如亨廷顿病等神经退行性疾病有关.
研究的目的:
- 为了研究心肌细胞内细胞内表达的可溶性前胺类寡合体 (PAO) 的细胞毒性.
- 测试心肌细胞受限PAO积累是否足以引起心力衰竭.
主要方法:
- 产生了具有心肌细胞自主表达的转基因小鼠,可以是83残留PQ重复 (PQ83) 或非致病性19残留PQ控制 (PQ19).
- 在表达PQ83和PQ19的小鼠之间比较心脏功能,形态和寿命.
- 分析了PQ83蛋白积累,侵略性细胞的形成,细胞死亡和自/溶酶体通路的标记.
主要成果:
- 表达PQ83的小鼠在8个月后心脏功能,扩张和死亡率降低.
- PQ19对照小鼠保持了正常的心脏功能,形态和寿命.
- 在侵略体中积聚的PQ83蛋白,心脏显示自/溶酶体标志物增加和细胞死亡指标.
结论:
- 这项研究证实,在心肌细胞中表达一种外源PAO形成是有毒的.
- 在小鼠模型中,心肌细胞受限的PAO表达足以诱导心肌细胞损失和心力衰竭.
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