Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Olav Kyrres Gate 9, 7491 Trondheim, Norway.
Instituto de Física del Sur (IFISUR), Departamento de Física, Universidad Nacional del Sur (UNS), CONICET, Av. L. N. Alem 1253, Bahía Blanca B8000CPB, Argentina.
Molecules. 2021 Dec 24;27(1):88. doi: 10.3390/molecules27010088.
The aggregation of proteins into amyloid fibers is linked to more than forty still incurable cellular and neurodegenerative diseases such as Parkinson's disease (PD), multiple system atrophy, Alzheimer's disease and type 2 diabetes, among others. The process of amyloid formation is a main feature of cell degeneration and disease pathogenesis. Despite being methodologically challenging, a complete understanding of the molecular mechanism of aggregation, especially in the early stages, is essential to find new biological targets for innovative therapies. Here, we reviewed selected examples on α-syn showing how complementary approaches, which employ different biophysical techniques and models, can better deal with a comprehensive study of amyloid aggregation. In addition to the monomer aggregation and conformational transition hypothesis, we reported new emerging theories regarding the self-aggregation of α-syn, such as the alpha-helix rich tetramer hypothesis, whose destabilization induce monomer aggregation; and the liquid-liquid phase separation hypothesis, which considers a phase separation of α-syn into liquid droplets as a primary event towards the evolution to aggregates. The final aim of this review is to show how multimodal methodologies provide a complete portrait of α-syn oligomerization and can be successfully extended to other protein aggregation diseases.
蛋白质聚集成淀粉样纤维与四十多种仍无法治愈的细胞和神经退行性疾病有关，如帕金森病 (PD)、多系统萎缩、阿尔茨海默病和 2 型糖尿病等。淀粉样形成过程是细胞退化和疾病发病机制的主要特征。尽管在方法学上具有挑战性，但全面了解聚合的分子机制，特别是在早期阶段，对于寻找创新疗法的新生物靶点至关重要。在这里，我们回顾了选定的α-突触核蛋白的例子，展示了如何使用不同的生物物理技术和模型的互补方法，可以更好地研究淀粉样蛋白的聚集。除了单体聚合和构象转变假说外，我们还报告了关于α-突触核蛋白自聚集的新出现理论，例如富含α-螺旋的四聚体假说，其不稳定性导致单体聚合；以及液-液相分离假说，它将α-突触核蛋白的液-液相分离视为向聚集物演变的主要事件。本综述的最终目的是展示多模态方法学如何提供α-突触核蛋白寡聚化的完整描述，并可成功扩展到其他蛋白质聚集疾病。
