Lindsten Kristina, Menéndez-Benito Victoria, Masucci Maria G, Dantuma Nico P
Microbiology and Tumor Biology Center, Karolinska Institutet, Box 280, S-171 77 Stockholm, Sweden.
Nat Biotechnol. 2003 Aug;21(8):897-902. doi: 10.1038/nbt851. Epub 2003 Jul 20.
Impairment of the ubiquitin/proteasome system has been proposed to play a role in neurodegenerative disorders such as Alzheimer and Parkinson diseases. Although recent studies confirmed that some disease-related proteins block proteasomal degradation, and despite the existence of excellent animal models of both diseases, in vivo data about the system are lacking. We have developed a model for in vivo analysis of the ubiquitin/proteasome system by generating mouse strains transgenic for a green fluorescent protein (GFP) reporter carrying a constitutively active degradation signal. Administration of proteasome inhibitors to the transgenic animals resulted in a substantial accumulation of GFP in multiple tissues, confirming the in vivo functionality of the reporter. Moreover, accumulation of the reporter was induced in primary neurons by UBB+1, an aberrant ubiquitin found in Alzheimer disease. These transgenic animals provide a tool for monitoring the status of the ubiquitin/proteasome system in physiologic or pathologic conditions.
泛素/蛋白酶体系统功能受损被认为在神经退行性疾病如阿尔茨海默病和帕金森病中发挥作用。尽管最近的研究证实一些疾病相关蛋白会阻碍蛋白酶体降解，并且这两种疾病都有出色的动物模型，但关于该系统的体内数据仍然缺乏。我们通过构建携带组成型活性降解信号的绿色荧光蛋白（GFP）报告基因的转基因小鼠品系，开发了一种用于体内分析泛素/蛋白酶体系统的模型。给转基因动物施用蛋白酶体抑制剂会导致GFP在多个组织中大量积累，证实了报告基因在体内的功能。此外，阿尔茨海默病中发现的异常泛素UBB +1可在原代神经元中诱导报告基因的积累。这些转基因动物为监测生理或病理条件下泛素/蛋白酶体系统的状态提供了一种工具。
