Cross-Seeding Controls Aβ Fibril Populations and Resulting Functions
Cross-Seeding Controls Aβ Fibril Populations and Resulting Functions
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DOI：
10.1021/acs.jpcb.1c09995
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发表时间：
2022-03-24
影响因子：
3.3
通讯作者：
Webb, Lauren J.
中科院分区：
文献类型：
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作者：
Lucas, Michael J.;Pan, Henry S.;Webb, Lauren J.
淀粉样肽从单体成核，通过初级成核聚集成原纤维。然后，预先存在的原纤维可以充当其他单体的种子，通过二次成核形成原纤维。两个成核过程同时发生，产生可产生一系列神经退行性效应的原纤维多晶型分布。了解在成核过程中驱动多晶型结构分布的机制对于揭示原纤维结构-功能关系以及在体外创建与体内发现的原纤维结构更好匹配的多晶型分布非常重要。在这里，我们探讨了野生型 (WT) A beta(1-40) 与 A beta(1-40) 突变体 E22G（北极）和 E22 Delta（大阪）以及 WT A(beta 1-42) 的交叉播种如何影响原纤维结构多态性的分布，以及结构分布的变化如何影响毒性。透射电子显微镜复制分析表明，源自 A beta(1-40) 突变体的原纤维种子在二次成核过程中将其结构传递给 WT A beta(1-40) 单体，但 WT A beta(1-40) 原纤维种子并不影响由突变体 A beta(1-40) 单体组装的原纤维的结构，尽管动力学数据表明当任何突变体组合交叉播种时会加速聚集。此外，用突变原纤维接种的WT A beta(1-40)原纤维产生了与具有相似细胞毒性特征的突变种子相似的结构分布。这表明突变原纤维种子不仅将其结构赋予生长的WT A beta(1-40)聚集体，而且还赋予细胞毒性特性。我们的研究结果在多晶型群体水平上建立了原纤维结构和表型之间的关系，并且这些特性可以通过二次成核传递给后续几代原纤维。
Amyloid peptides nucleate from monomers to aggregate into fibrils through primary nucleation. Pre-existing fibrils can then act as seeds for additional monomers to fibrillize through secondary nucleation. Both nucleation processes occur simultaneously, yielding a distribution of fibril polymorphs that can generate a spectrum of neurodegenerative effects. Understanding the mechanisms driving polymorph structural distribution during both nucleation processes is important for uncovering fibril structure-function relationships, as well as for creating polymorph distributions in vitro that better match fibril structures found in vivo. Here, we explore how cross-seeding wild-type (WT) A beta(1-40) with A beta(1-40) mutants E22G (Arctic) and E22 Delta (Osaka), as well as with WT A(beta 1-42), affects the distribution of fibril structural polymorphs and how changes in structural distribution impact toxicity. Transmission electron micros copy analysis revealed that fibril seeds derived from mutants of A beta(1-40) imparted their structure to WT A beta(1-40) monomers during secondary nucleation, but WT A beta(1-40) fibril seeds do not affect the structure of fibrils assembled from mutant A beta(1-40) monomers, despite the kinetic data indicating accelerated aggregation when cross-seeding of any combination of mutants. Additionally, WT A beta(1-40) fibrils seeded with mutant fibrils produced similar structural distributions to the mutant seeds with similar cytotoxicity profiles. This indicates that mutant fibril seeds not only impart their structure to growing WT A beta(1-40) aggregates but also impart cytotoxic properties. Our findings establish a relationship between the fibril structure and the phenotype on a polymorph population level and that these properties can be passed on through secondary nucleation to the succeeding generations of fibrils.