Physical and Materials Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
J Phys Chem B. 2022 Jul 7;126(26):4799-4813. doi: 10.1021/acs.jpcb.2c02203. Epub 2022 Jun 25.
Cellular stress is a major cause of neurodegenerative diseases. In particular, in amyotrophic lateral sclerosis (ALS), around 90% of the cases are believed to occur due to aggregation and misfolding of TDP-43 protein in neurons due to aging and chronic environmental stress. However, the physicochemical basis of how TDP-43 senses the change in solvation conditions during stress and misfolds remains very poorly understood. We show here that the full-length human TDP-43 can exist in equilibrium with multiple structural states. The equilibrium between these states is highly sensitive to changes in solvation conditions. We show that upon thermal and pH stress, amyloidogenic oligomers can form amyloid-like fibrils. However, the internal structure of the fibril depends upon the physicochemical nature of stress. Our results present a physical basis of the effect of solvation conditions on inter- and intramolecular assembly formation of TDP-43 and reconcile why the nature and the internal structure of the aggregated form have been found to be different when extracted from the brain of different ALS patients.
细胞应激是神经退行性疾病的主要原因。特别是在肌萎缩性侧索硬化症（ALS）中，据信大约 90%的病例是由于神经元中 TDP-43 蛋白的聚集和错误折叠引起的，这是由于衰老和慢性环境应激引起的。然而，TDP-43 在应激过程中如何感知溶剂化条件的变化并发生错误折叠的理化基础仍知之甚少。我们在这里表明，全长人 TDP-43 可以与多种结构状态处于平衡状态。这些状态之间的平衡对溶剂化条件的变化非常敏感。我们表明，在热和 pH 应激下，淀粉样寡聚体可以形成类似淀粉样的纤维。然而，纤维的内部结构取决于应激的物理化学性质。我们的结果提出了溶剂化条件对 TDP-43 分子间和分子内组装形成的影响的物理基础，并解释了为什么从不同 ALS 患者的大脑中提取的聚集形式的性质和内部结构不同。
