Abstract

Several studies recently showed that ex vivo fibrils from patient or animal tissue were structurally different from in vitro formed fibrils from the same polypeptide chain. Analysis of serum amyloid A (SAA) and Aβ-derived amyloid fibrils additionally revealed that ex vivo fibrils were more protease stable than in vitro fibrils. These observations gave rise to the proteolytic selection hypothesis that suggested that disease-associated amyloid fibrils were selected inside the body by their ability to resist endogenous clearance mechanisms. We here show, for more than twenty different fibril samples, that ex vivo fibrils are more protease stable than in vitro fibrils. These data support the idea of a proteolytic selection of pathogenic amyloid fibril morphologies and help to explain why only few amino acid sequences lead to amyloid diseases, although many, if not all, polypeptide chains can form amyloid fibrils in vitro.

摘要

最近的几项研究表明，来自患者或动物组织的离体原纤维在结构上与来自同一多肽链的体外形成的原纤维不同。对血清淀粉样蛋白 A (SAA) 和 Aβ 衍生的淀粉样蛋白原纤维的分析还表明，离体原纤维比体外原纤维更具有蛋白酶稳定性。这些观察产生了蛋白水解选择假说，该假说表明疾病相关的淀粉样蛋白原纤维是通过其抵抗内源性清除机制的能力在体内被选择的。我们在此显示，对于 20 多种不同的原纤维样品，离体原纤维比体外的蛋白酶更稳定原纤维。这些数据支持对致病性淀粉样原纤维形态进行蛋白水解选择的想法，并有助于解释为什么只有少数氨基酸序列会导致淀粉样蛋白疾病，尽管许多（如果不是全部）多肽链可以在体外形成淀粉样蛋白原纤维。