Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Central Research Laboratories, Sysmex Corporation, Kobe, Japan.
Sci Rep. 2024 Sep 3;14(1):20508. doi: 10.1038/s41598-024-71446-8.
The pathophysiology of variant transthyretin (TTR) amyloidosis (ATTRv) is associated with destabilizing mutations in the TTR tetramer. However, why TTR with a wild-type genetic sequence misfolds and aggregates in wild-type transthyretin amyloidosis (ATTRwt) is unknown. Here, we evaluate kinetic TTR stability with a newly developed ELISA system in combination with urea-induced protein denaturation. Compared with that in control patients, endogenous TTR in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) exhibited thermodynamic instability, indicating that circulating TTR instability may be associated with the pathogenesis of ATTRwt as well as ATTRv. Our findings provide new insight into the underlying mechanisms of ATTRwt.
变异转甲状腺素蛋白（TTR）淀粉样变（ATTRv）的病理生理学与 TTR 四聚体的不稳定突变有关。然而，为什么野生型 TTR 会发生错误折叠和聚集在野生型转甲状腺素蛋白淀粉样变（ATTRwt）中尚不清楚。在这里，我们使用新开发的 ELISA 系统结合尿素诱导的蛋白质变性来评估 TTR 的动力学稳定性。与对照患者相比，野生型转甲状腺素蛋白淀粉样心肌病（ATTRwt-CM）患者的内源性 TTR 表现出热力学不稳定性，这表明循环 TTR 的不稳定性可能与 ATTRwt 以及 ATTRv 的发病机制有关。我们的发现为 ATTRwt 的潜在机制提供了新的见解。
