人类 Z α1-抗胰蛋白酶缺乏症的肝细胞功能的转基因斑马鱼模型。
A transgenic zebrafish model of hepatocyte function in human Z α1-antitrypsin deficiency.
机构信息
Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne 3800, Victoria, Australia.
School of Biological Sciences, Monash University, Melbourne 3800, Victoria, Australia.
出版信息
Biol Chem. 2019 Nov 26;400(12):1603-1616. doi: 10.1515/hsz-2018-0391.
In human α1-antitrypsin deficiency, homozygous carriers of the Z (E324K) mutation in the gene SERPINA1 have insufficient circulating α1-antitrypsin and are predisposed to emphysema. Misfolding and accumulation of the mutant protein in hepatocytes also causes endoplasmic reticulum stress and underpins long-term liver damage. Here, we describe transgenic zebrafish (Danio rerio) expressing the wildtype or the Z mutant form of human α1-antitrypsin in hepatocytes. As observed in afflicted humans, and in rodent models, about 80% less α1-antitrypsin is evident in the circulation of zebrafish expressing the Z mutant. Although these zebrafish also show signs of liver stress, they do not accumulate α1-antitrypsin in hepatocytes. This new zebrafish model will provide useful insights into understanding and treatment of α1-antitrypsin deficiency.
在人类α1-抗胰蛋白酶缺乏症中，SERPINA1 基因中 Z（E324K）突变的纯合子携带者循环中的α1-抗胰蛋白酶不足，易患肺气肿。突变蛋白在肝细胞中的错误折叠和积累也会导致内质网应激，并构成长期肝损伤的基础。在这里，我们描述了在肝细胞中表达野生型或 Z 突变型人α1-抗胰蛋白酶的转基因斑马鱼（Danio rerio）。正如在受影响的人类和啮齿动物模型中观察到的那样，表达 Z 突变体的斑马鱼中循环中的α1-抗胰蛋白酶明显减少了约 80%。尽管这些斑马鱼也表现出肝应激的迹象，但它们不会在肝细胞中积累α1-抗胰蛋白酶。这种新的斑马鱼模型将为理解和治疗α1-抗胰蛋白酶缺乏症提供有用的见解。
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