Heterotypic Amyloid β interactions facilitate amyloid assembly and modify amyloid structure
Heterotypic Amyloid β interactions facilitate amyloid assembly and modify amyloid structure
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DOI：
10.15252/embj.2021108591
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发表时间：
2021-11-29
期刊：
影响因子：
11.4
通讯作者：
Rousseau, Frederic
中科院分区：
文献类型：
--
作者：
Konstantoulea, Katerina;Guerreiro, Patricia;Rousseau, Frederic
目前尚不清楚为什么病理性淀粉样蛋白沉积在特定的大脑区域开始，或者为什么某些细胞或组织比其他细胞或组织更容易受到影响。淀粉样蛋白沉积是由称为易聚集区域（APR）的短蛋白质片段的自组装决定的，这些短蛋白质片段有利于交叉β结构。在这里，我们研究了 Aβ 淀粉样蛋白组装是否可以通过 AβAPR 与其他不相关的人类蛋白质中的短同源片段之间的异型相互作用进行修饰。挖掘 AD 患者 Aβ 斑块的现有蛋白质组学数据揭示了与 Aβ APR 具有同源序列的蛋白质的富集，表明患者中可能发生异型淀粉样蛋白相互作用。我们从这些蛋白质中鉴定出同源 APR，并表明它们可以在体外改变 Aβ 组装动力学、原纤维形态和沉积模式。此外，我们发现其中三种蛋白质在 A β 报告细胞系中瞬时表达后会促进 A β 淀粉样蛋白聚集。引人注目的是，我们没有发现 AD 小鼠模型中观察到 Aβ 自聚集的斑块存在异型相互作用的偏差。基于这些数据，我们提出异型 APR 相互作用可能在淀粉样蛋白沉积疾病中发挥迄今为止尚未实现的作用。
It is still unclear why pathological amyloid deposition initiates in specific brain regions or why some cells or tissues are more susceptible than others. Amyloid deposition is determined by the self-assembly of short protein segments called aggregation-prone regions (APRs) that favour cross-beta structure. Here, we investigated whether A beta amyloid assembly can be modified by heterotypic interactions between A beta APRs and short homologous segments in otherwise unrelated human proteins. Mining existing proteomics data of A beta plaques from AD patients revealed an enrichment in proteins that harbour such homologous sequences to the A beta APRs, suggesting heterotypic amyloid interactions may occur in patients. We identified homologous APRs from such proteins and show that they can modify A beta assembly kinetics, fibril morphology and deposition pattern in vitro. Moreover, we found three of these proteins upon transient expression in an A beta reporter cell line promote A beta amyloid aggregation. Strikingly, we did not find a bias towards heterotypic interactions in plaques from AD mouse models where A beta self-aggregation is observed. Based on these data, we propose that heterotypic APR interactions may play a hitherto unrealized role in amyloid-deposition diseases.