Pierangelini Andrea, Kessler Benedikt M, O'Brien Darragh P
Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Mol Cell Proteomics. 2025 Jun 20;24(8):101017. doi: 10.1016/j.mcpro.2025.101017.
Human neurodegenerative conditions such as Parkinson's and Alzheimer's disease are characterized by the formation and deposition of toxic protein species which exacerbate neuronal dysfunction, impacting the structure and function of the healthy brain. Deciphering the mechanisms underlying protein (mis)folding and aggregation is not only essential for a more coherent view of neurodegeneration, but also crucial for the development of novel therapeutics targeting this family of disorders. Key pathological drivers of neurodegeneration, such as alpha-synuclein and tau proteins, have traditionally proved extremely challenging to characterize structurally due to their intrinsic and widespread structural plasticity. Hydrogen-Deuterium eXchange Mass Spectrometry has emerged as a powerful tool to help circumvent this, owing to its ability to capture protein intrinsic disorder in solution, in addition to the transient structural conformations that typify protein aggregation pathways. This review brings together the most recent research where Hydrogen-Deuterium eXchange Mass Spectrometry has shed light on mechanisms of neurodegeneration. We highlight how the technique has been successfully integrated into therapeutic development workflows targeting some of the most prevalent neurodegenerative diseases.
人类神经退行性疾病，如帕金森病和阿尔茨海默病，其特征在于有毒蛋白质种类的形成和沉积，这些蛋白质会加剧神经元功能障碍，影响健康大脑的结构和功能。解读蛋白质（错误）折叠和聚集背后的机制，不仅对于更全面地理解神经退行性变至关重要，而且对于开发针对这类疾病的新型疗法也至关重要。传统上，神经退行性变的关键病理驱动因素，如α-突触核蛋白和tau蛋白，由于其内在的广泛结构可塑性，在结构表征方面极具挑战性。氢-氘交换质谱法已成为一种强大的工具来帮助解决这一问题，这是因为它不仅能够捕捉溶液中蛋白质的内在无序状态，还能捕捉代表蛋白质聚集途径的瞬态结构构象。本综述汇集了氢-氘交换质谱法在揭示神经退行性变机制方面的最新研究。我们重点介绍了该技术如何成功地整合到针对一些最常见神经退行性疾病的治疗开发流程中。
