School of Chemistry, Indian Institute of Science Education and Research Thiruvananthapuram (IISER TVM) Vithura, Thiruvananthapuram695551,India.
ACS Chem Neurosci. 2024 Mar 20;15(6):1242-1253. doi: 10.1021/acschemneuro.3c00852. Epub 2024 Mar 3.
The initial stages of amyloid fibrilization begin with the monomers populating aggregation-prone conformers. Characterization of such aggregation-prone conformers is crucial in the study of neurodegenerative diseases. The current study characterizes the aggregation pathway of two tau protein constructs that have been recently demonstrated to form Alzheimer's (AD) fibril structures with divalent ions and chronic traumatic encephalopathy (CTE) fibril structures with monovalent ions. The results highlight the involvement of identical residues in both the primary and secondary processes of both AD and CTE fibril propagation. Nuclear magnetic resonance relaxation experiments reveal increased flexibility of the motifs KCGS within R3 and PGGGN within R4 in the presence of MgCl/NaCl, correlating with faster aggregation kinetics and indicating efficient primary nucleation. Notably, the seeded aggregation kinetics of the tau monomers in the presence and absence of metal ions are strikingly different. This correlates with the overall sign of the NΔ profile specifying the dominant mechanism involved in the process of aggregation.
淀粉样纤维形成的初始阶段始于单体填充聚集倾向构象。对这种聚集倾向构象的特征描述对于神经退行性疾病的研究至关重要。本研究描述了两种 tau 蛋白构建体的聚集途径，最近的研究表明，这两种构建体在二价离子存在下形成阿尔茨海默病（AD）纤维结构，在单价离子存在下形成慢性创伤性脑病（CTE）纤维结构。研究结果强调了相同残基在 AD 和 CTE 纤维传播的主要和次要过程中的参与。核磁共振弛豫实验表明，在 MgCl/NaCl 存在下，R3 中的 KCGS 基序和 R4 中的 PGGGN 变得更加灵活，这与更快的聚集动力学相关，并表明有效的初级成核。值得注意的是，在有和没有金属离子的情况下，tau 单体的接种聚集动力学有显著差异。这与 NΔ 曲线的整体符号相关，该符号指定了在聚集过程中涉及的主要机制。
