Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, United States.
Department of Entomology, Texas A&M University, College Station, Texas 77843, United States.
ACS Chem Neurosci. 2023 Sep 20;14(18):3499-3506. doi: 10.1021/acschemneuro.3c00357. Epub 2023 Sep 7.
The progressive accumulation of transthyretin (TTR), a small protein that transports thyroxine, in various organs and tissues is observed upon transthyretin amyloidosis, a severe pathology that affects the central, peripheral, and autonomic nervous systems. Once expressed in the liver and choroid plexus, TTR is secreted into the bloodstream and cerebrospinal fluid. In addition to thyroxine, TTR interacts with a large number of molecules, including retinol-binding protein and lipids. In this study, we examined the extent to which phosphatidylserine (PS), a phospholipid that is responsible for the recognition of apoptotic cells by macrophages, could alter the stability of TTR. Using thioflavin T assay, we investigated the rates of TTR aggregation in the presence of PS with different lengths and saturation of fatty acids (FAs). We found that all analyzed lipids decelerated the rate of TTR aggregation. We also used a set of biophysical methods to investigate the extent to which the presence of PS altered the morphology and secondary structure of TTR aggregates. Our results showed that the length and saturation of fatty acids in PS uniquely altered the morphology and secondary structure of TTR fibrils. As a result, TTR fibrils that were formed in the presence of PS with different lengths and saturation of FAs exerted significantly lower cell toxicity compared with the TTR aggregates grown in the lipid-free environment. These findings help to reveal the role of PS in transthyretin amyloidosis and determine the role of the length and saturation of FAs in PS on the morphology and secondary structure of TTR fibrils.
转甲状腺素蛋白（TTR）在各种器官和组织中的逐渐积累是转甲状腺素蛋白淀粉样变性的表现，这是一种严重的病理学疾病，会影响中枢、外周和自主神经系统。TTR 在肝脏和脉络丛中表达后，会被分泌到血液和脑脊液中。除了甲状腺素，TTR 还与大量分子相互作用，包括视黄醇结合蛋白和脂质。在这项研究中，我们研究了磷脂酰丝氨酸（PS）——一种负责巨噬细胞识别凋亡细胞的磷脂——能够在多大程度上改变 TTR 的稳定性。我们使用硫黄素 T 检测法，研究了在具有不同脂肪酸（FAs）长度和饱和度的 PS 存在下 TTR 聚集的速率。我们发现所有分析的脂质都减缓了 TTR 聚集的速率。我们还使用了一组生物物理方法来研究 PS 的存在在多大程度上改变了 TTR 聚集体的形态和二级结构。我们的结果表明，PS 中脂肪酸的长度和饱和度独特地改变了 TTR 原纤维的形态和二级结构。因此，与在无脂质环境中生长的 TTR 聚集体相比，在具有不同长度和饱和度的 FAs 的 PS 存在下形成的 TTR 原纤维对细胞的毒性明显降低。这些发现有助于揭示 PS 在转甲状腺素蛋白淀粉样变性中的作用，并确定 PS 中 FAs 的长度和饱和度对 TTR 原纤维形态和二级结构的作用。
