Herrera María G, Ciccone Lidia, Moleiro Lara H, Tonali Nicolo, Dodero Verónica Isabel
Laboratorio de Genómica e Ingeniería de Sistemas Biológicos, Instituto de Biociencias, Biotecnología y Biología Traslacional (iB3), Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Intendente Güiraldes 2160, Ciudad Autónoma de Buenos Aires C1428EGA, Argentina.
Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Bochum 44801, Germany.
ACS Nano. 2025 Sep 2;19(34):30688-30719. doi: 10.1021/acsnano.5c01662. Epub 2025 Aug 8.
The self-assembly of endogenous and exogenous peptides into proteolysis-resistant oligomers can trigger toxic cellular events and diseases. In Alzheimer's disease (AD), the structural polymorphisms of endogenous amyloid-β (Aβ) 1-40 and 1-42 aggregates are essential for their neurotoxic effects. Recent findings on structural differences between brain-derived and fibrils underscore the need to improve the molecular and supramolecular models of diseases, for example, by stabilizing monomer conformations that lead to disease-relevant structures. In gluten-related disorders (GRDs), particularly celiac disease (CeD), research focuses on exogenous proteolytically resistant gliadin peptides (PRGPs) such as the 33-mer, p31-43, and pepsin-trypsin-derived gliadin peptides. Notably, these PRGPs form nanostructures, which may explain their behavior as nonreplicating pathogens. Thus, understanding their self-assembly has recently gained attention. This review invites both newcomers and experts in the field to tackle the challenges of characterizing peptide self-assembly process as first step to develop successful therapeutic interventions. For AD researchers, it highlights protocols for obtaining monomers and their supramolecular characterization to uncover mechanisms of brain-derived fibril formation, while also showcasing opportunities to explore PRGP nanostructures. For GRD researchers, it offers protocols to obtain PRGP nanostructures and their thorough characterization prior to cellular studies, inspired by approaches in AD research. This review contributes to interdisciplinary efforts toward therapeutic strategies grounded in molecular and supramolecular data by outlining structural insights, characterization protocols, and existing knowledge gaps. Its final aim is to connect established and emerging research domains related to Aβ and gliadin peptides that may have potential applications in peptide self-assembly and the gut-brain axis research, respectively.
内源性和外源性肽自组装成抗蛋白水解的寡聚体可引发毒性细胞事件和疾病。在阿尔茨海默病（AD）中，内源性淀粉样β蛋白（Aβ）1-40和1-42聚集体的结构多态性对其神经毒性作用至关重要。最近关于脑源性纤维与其他纤维结构差异的研究结果强调了改进疾病分子和超分子模型的必要性，例如，通过稳定导致疾病相关结构的单体构象。在麸质相关疾病（GRD）中，尤其是乳糜泻（CeD），研究重点是外源性抗蛋白水解麦醇溶蛋白肽（PRGP），如33聚体、p31-43和胃蛋白酶-胰蛋白酶衍生的麦醇溶蛋白肽。值得注意的是，这些PRGP形成纳米结构，这可能解释了它们作为非复制性病原体的行为。因此，了解它们的自组装最近受到了关注。本综述邀请该领域的新手和专家应对表征肽自组装过程的挑战，这是开发成功治疗干预措施的第一步。对于AD研究人员，它强调了获取单体及其超分子表征以揭示脑源性纤维形成机制的方案，同时还展示了探索PRGP纳米结构的机会。对于GRD研究人员，它提供了受AD研究方法启发，在细胞研究之前获取PRGP纳米结构及其全面表征的方案。本综述通过概述结构见解、表征方案和现有知识空白，为基于分子和超分子数据的治疗策略的跨学科努力做出了贡献。其最终目的是连接与Aβ和麦醇溶蛋白肽相关的已建立和新兴研究领域，它们可能分别在肽自组装和肠-脑轴研究中有潜在应用。
