Kulenkampff Klara, Wolf Perez Adriana-M, Sormanni Pietro, Habchi Johnny, Vendruscolo Michele
Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, UK.
Nat Rev Chem. 2021 Apr;5(4):277-294. doi: 10.1038/s41570-021-00254-9. Epub 2021 Feb 15.
Protein misfolding and aggregation are characteristic of a wide range of neurodegenerative disorders, including Alzheimer and Parkinson diseases. A hallmark of these diseases is the aggregation of otherwise soluble and functional proteins into amyloid aggregates. Although for many decades such amyloid deposits have been thought to be responsible for disease progression, it is now increasingly recognized that the misfolded protein oligomers formed during aggregation are, instead, the main agents causing pathological processes. These oligomers are transient and heterogeneous, which makes it difficult to detect and quantify them, generating confusion about their exact role in disease. The lack of suitable methods to address these challenges has hampered efforts to investigate the molecular mechanisms of oligomer toxicity and to develop oligomer-based diagnostic and therapeutic tools to combat protein misfolding diseases. In this Review, we describe methods to quantify misfolded protein oligomers, with particular emphasis on diagnostic applications as disease biomarkers and on therapeutic applications as target biomarkers. The development of these methods is ongoing, and we discuss the challenges that remain to be addressed to establish measurement tools capable of overcoming existing limitations and to meet present needs.
蛋白质错误折叠和聚集是多种神经退行性疾病的特征，包括阿尔茨海默病和帕金森病。这些疾病的一个标志是原本可溶且有功能的蛋白质聚集成淀粉样聚集体。尽管几十年来人们一直认为这种淀粉样沉积物是疾病进展的原因，但现在越来越认识到，聚集过程中形成的错误折叠蛋白寡聚体才是导致病理过程的主要因素。这些寡聚体是短暂且异质的，这使得检测和量化它们变得困难，也让人对它们在疾病中的确切作用产生困惑。缺乏应对这些挑战的合适方法阻碍了人们对寡聚体毒性分子机制的研究，以及开发基于寡聚体的诊断和治疗工具来对抗蛋白质错误折叠疾病的努力。在这篇综述中，我们描述了量化错误折叠蛋白寡聚体的方法，特别强调其作为疾病生物标志物的诊断应用以及作为靶点生物标志物的治疗应用。这些方法仍在不断发展，我们讨论了在建立能够克服现有局限性并满足当前需求的测量工具方面仍有待解决的挑战。
