Tomar Vijay Raj, Sharma Shilpa, Siddhanta Soumik, Deep Shashank
Department of Chemistry, Indian Institute of Technology Delhi, New Delhi, India.
Commun Chem. 2025 Jan 28;8(1):22. doi: 10.1038/s42004-025-01421-5.
Superoxide dismutase 1 (SOD1) aggregation is implicated in the development of Amyotrophic Lateral Sclerosis (ALS). Despite knowledge of the role of SOD1 aggregation, the mechanistic understanding remains elusive. Our investigation aimed to unravel the complex steps involved in SOD1 aggregation associated with ALS. Therefore, we probed the aggregation using ThT fluorescence, size-exclusion chromatography, and surface-enhanced Raman spectroscopy (SERS). The removal of metal ions and disulfide bonds resulted in the dimers rapidly first converting to an extended monomers then coming together slowly to form non-native dimers. The rapid onset of oligomerization happens above critical non-native dimer concentration. Structural features of oligomer was obtained through SERS. The kinetic data supported a fragmentation-dominant mechanism for the fibril formation. Quercetin acts as inhibitor by delaying the formation of non-native dimer and soluble oligomers by decreasing the elongation rate. Thus, results provide significant insights into the critical steps in oligomer formation and their structure.
超氧化物歧化酶1（SOD1）聚集与肌萎缩侧索硬化症（ALS）的发展有关。尽管了解SOD1聚集的作用，但对其机制的理解仍然难以捉摸。我们的研究旨在揭示与ALS相关的SOD1聚集中涉及的复杂步骤。因此，我们使用硫黄素T荧光、尺寸排阻色谱和表面增强拉曼光谱（SERS）来探测聚集情况。去除金属离子和二硫键后，二聚体首先迅速转化为伸展的单体，然后缓慢聚集形成非天然二聚体。寡聚化的快速发生发生在临界非天然二聚体浓度以上。通过SERS获得了寡聚物的结构特征。动力学数据支持了纤维形成的碎片化主导机制。槲皮素通过降低伸长率来延迟非天然二聚体和可溶性寡聚物的形成，从而起到抑制剂的作用。因此，研究结果为寡聚物形成的关键步骤及其结构提供了重要见解。
