Kaneko K, Ball H L, Wille H, Zhang H, Groth D, Torchia M, Tremblay P, Safar J, Prusiner S B, DeArmond S J, Baldwin M A, Cohen F E
Institute for Neurodegenerative Diseases, Department of Neurology, University of California, San Francisco, 94143, USA.
J Mol Biol. 2000 Jan 28;295(4):997-1007. doi: 10.1006/jmbi.1999.3386.
The molecular basis of the infectious, inherited and sporadic forms of prion diseases is best explained by a conformationally dimorphic protein that can exist in distinct normal and disease-causing isoforms. We identified a 55-residue peptide of a mutant prion protein that can be refolded into at least two distinct conformations. When inoculated intracerebrally into the appropriate transgenic mouse host, 20 of 20 mice receiving the beta-form of this peptide developed signs of central nervous system dysfunction at approximately 360 days, with neurohistologic changes that are pathognomonic of Gerstmann-Sträussler-Scheinker disease. By contrast, eight of eight mice receiving a non-beta-form of the peptide failed to develop any neuropathologic changes more than 600 days after the peptide injections. We conclude that a chemically synthesized peptide refolded into the appropriate conformation can accelerate or possibly initiate prion disease.
朊病毒疾病的传染性、遗传性和散发性形式的分子基础，最好用一种构象双态蛋白来解释，该蛋白可以以不同的正常和致病异构体形式存在。我们鉴定出一种突变朊病毒蛋白的55个氨基酸残基的肽段，它可以重折叠成至少两种不同的构象。当将这种肽段的β形式脑内接种到合适的转基因小鼠宿主中时，20只接受该肽段β形式的小鼠中有20只在大约360天时出现中枢神经系统功能障碍的迹象，伴有格斯特曼-施特劳斯勒-谢inker病的特征性神经组织学变化。相比之下，8只接受该肽段非β形式的小鼠在肽段注射后600多天没有出现任何神经病理学变化。我们得出结论，化学合成的肽段重折叠成合适的构象可以加速或可能引发朊病毒疾病。
