Seira Curto Jofre, Dominguez Martinez Adan, Perez Collell Genis, Barniol Simon Estrella, Romero Ruiz Marina, Franco Bordés Berta, Sotillo Sotillo Paula, Villegas Hernandez Sandra, Fernandez Maria Rosario, Sanchez de Groot Natalia
Unitat de Bioquímica, Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain.
Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, 08193, Spain.
Mol Syst Biol. 2025 May 27. doi: 10.1038/s44320-025-00114-4.
The gut is exposed to a wide range of proteins, including ingested proteins and those produced by the resident microbiota. While ingested prion-like proteins can propagate across species, their implications for disease development remain largely unknown. Here, we apply a multidisciplinary approach to examine the relationship between the biophysical properties of exogenous prion-like proteins and the phenotypic consequences of ingesting them. Through computational analysis of gut bacterial proteins, we identified an enrichment of prion-like sequences in Helicobacter pylori. Based on these findings, we rationally designed a set of synthetic prion-like sequences that form amyloid fibrils, interfere with amyloid-beta-peptide aggregation, and trigger prion propagation when introduced in the yeast Sup35 model. When C. elegans were fed bacteria expressing these prion-like proteins, they lost associative memory and exhibited increased lipid oxidation. These data suggest a link between memory impairment, the conformational state of aggregates, and oxidative stress. Overall, this work supports gut microbiota as a reservoir of exogenous prion-like sequences, especially H. pylori, and the gut as an entry point for molecules capable of triggering cognitive dysfunction.
肠道会接触到各种各样的蛋白质，包括摄入的蛋白质以及肠道常驻微生物群产生的蛋白质。虽然摄入的朊病毒样蛋白可以跨物种传播，但其对疾病发展的影响在很大程度上仍不为人知。在此，我们采用多学科方法来研究外源性朊病毒样蛋白的生物物理特性与摄入这些蛋白后的表型后果之间的关系。通过对肠道细菌蛋白质的计算分析，我们在幽门螺杆菌中发现了朊病毒样序列的富集。基于这些发现，我们合理设计了一组能形成淀粉样纤维、干扰β-淀粉样肽聚集并在酵母Sup35模型中引入时触发朊病毒传播的合成朊病毒样序列。当秀丽隐杆线虫喂食表达这些朊病毒样蛋白的细菌时，它们失去了联想记忆并表现出脂质氧化增加。这些数据表明记忆障碍、聚集体的构象状态和氧化应激之间存在联系。总体而言，这项研究支持肠道微生物群作为外源性朊病毒样序列的储存库，尤其是幽门螺杆菌，以及肠道作为能够引发认知功能障碍的分子的入口点。
