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首页> 外文期刊>Journal of Molecular Biology >Neutralizing Mutations Significantly Inhibit Amyloid Formation by Human Prion Protein and Decrease Its Cytotoxicity
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Neutralizing Mutations Significantly Inhibit Amyloid Formation by Human Prion Protein and Decrease Its Cytotoxicity

机译：中和突变显着抑制人朊病毒蛋白的淀粉样蛋白形成，降低其细胞毒性

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摘要

Prion diseases, such as Creutzfeldt Jakob disease and bovine spongiform encephalopathy, are fatal neurodegenerative diseases that affect many mammals including humans and are caused by the misfolding of prion protein (PrP). A naturally occurring protective polymorphism G127V in human PrP has recently been found to significantly attenuate prion diseases, but the mechanism has remained elusive. We herein report that the hydrophobic chain introduced in G127V significantly inhibits amyloid fibril formation by human PrP, highlighting the protective effect of the G127V polymorphism. We further introduce an amino acid with a different hydrophobic chain (Ile) at the same position and find that G1271 has similar protective effects as G127V. Moreover, we show that these two neutralizing mutations, G127V and G1271, significantly decrease the human PrP cytotoxicity resulting from PrP fibril formation, mitochondrial damage, and elevated reactive oxygen species production enhanced by a strong prion-prone peptide PrP 106-126. These findings elucidate the molecular basis for a natural protective polymorphism in PrP and will enable the development of novel therapeutic strategies against prion diseases. (C) 2019 Elsevier Ltd. All rights reserved.
机译：朊病毒疾病，如Creutzfeldt jakob疾病和牛海绵状脑病，是致命的神经变性疾病，这些疾病影响了许多哺乳动物，包括人类，是由朊病毒蛋白质（PRP）的错误折叠引起的。最近发现人类PRP的天然存在的保护性多态性G127V显着衰减朊病毒疾病，但该机制仍然难以捉摸。在此报道中，G127V中引入的疏水链显着抑制人PRP的淀粉样蛋白原纤维形成，突出了G127V多态性的保护作用。我们进一步在相同位置将氨基酸与不同的疏水链（ILE）引入并发现G1271具有与G127V相似的保护效果。此外，我们表明这两种中和突变，G127V和G1271，显着降低了由PRP原纤维形成，线粒体损伤和强化朊病毒肽PRP 106-126增强的活性氧物种生产产生的人PrP细胞毒性。这些研究结果阐明了PRP中的天然保护多态性的分子基础，并将能够开发对朊病毒疾病的新疗法策略。 （c）2019 Elsevier Ltd.保留所有权利。

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