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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Highly neurotoxic monomeric a-helical prion protein
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Highly neurotoxic monomeric a-helical prion protein

机译：高度神经毒性的单体α-螺旋病毒蛋白

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摘要

Prion diseases are infectious and belong to the group of protein misfolding neurodegenerative diseases. In these diseases, neuro-nal dysfunction and death are caused by the neuronal toxicity of a particular misfolded form of their cognate protein. The ability to specifically target the toxic protein conformer or the neuronal death pathway would provide powerful therapeutic approaches to these diseases. The neurotoxic forms of the prion protein (PrP) have yet to be defined but there is evidence suggesting that at least some of them differ from infectious PrP (PrP~(Sc)). Herein, without making an assumption about size or conformation, we searched for toxic forms of recombinant PrP after dilution refolding, size fractionation, and systematic biological testing of all fractions. We found that the PrP species most neurotoxic in vitro and in vivo (toxic PrP, TPrP) is a monomeric, highly α-helical form of PrP. TPrP caused autophagy, apoptosis, and a molecular signature remarkably similar to that observed in the brains of prion-infected animals. Interestingly, highly a-helical intermediates have been described for other amyloidogenic proteins but their biological significance remains to be established. We provide unique experimental evidence that a monomeric a-helical form of an amyloidogenic protein represents a cytotoxic species. Although toxic PrP has yet to be purified from prion-infected brains, TPrP might be the equivalent of one highly neurotoxic PrP species generated during prion replication. Because TPrP is a misfolded, highly neurotoxic form of PrP reproducing several features of prion-induced neuronal death, it constitutes a useful model to study PrP-induced neurodegenerative mechanisms.
机译：on病毒是传染性疾病，属于蛋白质折叠错误的神经退行性疾病。在这些疾病中，神经元功能障碍和死亡是由其关联蛋白的特定错误折叠形式引起的神经元毒性引起的。特异性靶向毒性蛋白构象异构体或神经元死亡途径的能力将为这些疾病提供强有力的治疗方法。 ion病毒蛋白（PrP）的神经毒性形式尚待确定，但有证据表明它们中至少有一部分与传染性PrP（PrP〜（Sc））不同。在此，在不假设大小或构象的情况下，我们在稀释重折叠，大小分级分离和所有级分的系统生物学测试后，搜索了有毒形式的重组PrP。我们发现，在体外和体内对神经毒性最强的PrP物种（毒性PrP，TPrP）是PrP的单体，高度α螺旋形式。 TPrP引起自噬，凋亡和分子标记，与to病毒感染动物的大脑中观察到的极为相似。有趣的是，已经描述了其他淀粉样蛋白的高度α-螺旋中间体，但其生物学意义仍有待确定。我们提供独特的实验证据，即淀粉样蛋白生成蛋白的单体a螺旋形式代表细胞毒性物质。尽管尚未从感染病毒的大脑中纯化出有毒的PrP，但TPrP可能相当于在病毒复制过程中产生的一种高度神经毒性的PrP物种。由于TPrP是PrP的错误折叠，高度神经毒性的形式，可重现病毒诱导的神经元死亡的几个特征，因此它构成了研究PrP诱导的神经退行性机制的有用模型。

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