Cofactors influence the biological properties of infectious recombinant prions
Cofactors influence the biological properties of infectious recombinant prions
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DOI：
10.1007/s00401-017-1782-y
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发表时间：
2018-02-01
影响因子：
12.7
通讯作者：
Castilla, Joaquin
中科院分区：
文献类型：
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作者：
Fernandez-Borges, Natalia;Di Bari, Michele A.;Castilla, Joaquin
朊病毒疾病是由细胞朊病毒蛋白（PrP）错误折叠为称为PrPSc的致病性同种型引起的。朊病毒作为菌株存在，其特征在于可能编码在PrPSc的三维结构中的特定病理和生化性质。然而，辅因子是否决定这些不同的PrPSc构象，以及这与其特定的生物学特性的关系在很大程度上是未知的。为了理解不同的辅因子如何调节朊病毒株的产生和选择，使用蛋白质错误折叠循环扩增通过在脑匀浆存在下繁殖来产生多种感染性重组朊病毒株。已知脑匀浆含有这些提到的辅因子，其身份仅部分已知，并且其促进PrPC转化为PrPSc。因此，我们获得了可区分的感染性朊病毒菌株的混合物。随后，我们用不同的聚阴离子辅因子取代了脑匀浆，这些辅因子能够驱动混合朊病毒种群向特定菌株进化。因此，我们的结果表明，多种感染性重组朊病毒可以在体外产生，并且它们的特定类型的构象，即，应变取决于在繁殖过程中可用的辅因子。这些观察对于理解朊病毒疾病的发病机制及其在不同组织和宿主中复制的能力具有重要意义。重要的是，这些考虑可能适用于其他神经退行性疾病，其中错误折叠蛋白质的不同构象已被描述。
Prion diseases are caused by a misfolding of the cellular prion protein (PrP) to a pathogenic isoform named PrPSc. Prions exist as strains, which are characterized by specific pathological and biochemical properties likely encoded in the three-dimensional structure of PrPSc. However, whether cofactors determine these different PrPSc conformations and how this relates to their specific biological properties is largely unknown. To understand how different cofactors modulate prion strain generation and selection, Protein Misfolding Cyclic Amplification was used to create a diversity of infectious recombinant prion strains by propagation in the presence of brain homogenate. Brain homogenate is known to contain these mentioned cofactors, whose identity is only partially known, and which facilitate conversion of PrPC to PrPSc. We thus obtained a mix of distinguishable infectious prion strains. Subsequently, we replaced brain homogenate, by different polyanionic cofactors that were able to drive the evolution of mixed prion populations toward specific strains. Thus, our results show that a variety of infectious recombinant prions can be generated in vitro and that their specific type of conformation, i.e., the strain, is dependent on the cofactors available during the propagation process. These observations have significant implications for understanding the pathogenesis of prion diseases and their ability to replicate in different tissues and hosts. Importantly, these considerations might apply to other neurodegenerative diseases for which different conformations of misfolded proteins have been described.