von der Haar Tobias, Jossé Lyne, Wright Paul, Zenthon Jo, Tuite Mick F
Protein Science Group, Department of Biosciences, University of Kent, Canterbury, UK.
Neurodegener Dis. 2007;4(2-3):136-47. doi: 10.1159/000101838.
Alzheimer's disease is the most common neurodegenerative disease, affecting approximately 50% of humans by age 85. The disease process is associated with aggregation of the Abeta peptides, short 39-43 residue peptides generated through endoproteolytic cleavage of the Alzheimer's precursor protein. While the process of aggregation of purified Abeta peptides in vitro is beginning to be well understood, little is known about this process in vivo. In the present study, we use the yeast Saccharomyces cerevisiae as a model system for studying Abeta-mediated aggregation in an organism in vivo. One of this yeast's endogenous prions, Sup35/[PSI+], loses the ability to aggregate when the prion-forming domain of this protein is deleted. We show that insertion of Abeta peptide sequences in place of the original prion domain of this protein restores its ability to aggregate. However, the aggregates are qualitatively different from [PSI+] prions in their sensitivity to detergents and in their requirements on trans-acting factors that are normally needed for [PSI+] propagation. We conclude that we have established a useful new tool for studying the aggregation of Abeta peptides in an organism in vivo.
阿尔茨海默病是最常见的神经退行性疾病，到85岁时约50%的人会受其影响。该疾病进程与β淀粉样肽的聚集有关，β淀粉样肽是由阿尔茨海默病前体蛋白经内切蛋白水解切割产生的39 - 43个氨基酸残基的短肽。虽然纯化的β淀粉样肽在体外的聚集过程已开始被充分了解，但对其在体内的这一过程却知之甚少。在本研究中，我们使用酿酒酵母作为模型系统来研究β淀粉样肽在生物体内介导的聚集。这种酵母的一种内源性朊病毒Sup35/[PSI+]，当该蛋白的朊病毒形成结构域被删除时，就会失去聚集能力。我们表明，插入β淀粉样肽序列来取代该蛋白原来的朊病毒结构域可恢复其聚集能力。然而，这些聚集体在对去污剂的敏感性以及对[PSI+]传播通常所需的反式作用因子的需求方面，在性质上与[PSI+]朊病毒不同。我们得出结论，我们已经建立了一种有用的新工具，用于研究β淀粉样肽在生物体内的聚集。
