转甲状腺素单体:症状前转甲状腺素相关淀粉样变性的新血浆生物标记物。

IF 5.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Diogo Costa-Rodrigues, José P Leite, Maria João Saraiva, Maria Rosário Almeida, Luís Gales
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引用次数: 0

摘要

背景:基因分型和组织中淀粉样纤维的检测通常被认为是转甲状腺素相关淀粉样变性病的诊断金标准。患者携带的 TTR 均四聚体稳定性较差,容易解离成非原生单体,并迅速自组装成低聚体,最终形成淀粉样纤维。因此,淀粉样蛋白级联的初始过程会产生最小的转甲状腺素:单体。这为诊断创造了尚未探索的工程机会:方法:我们假设分子筛是从血浆样本中的四聚体中分离和浓缩痕量 TTR 单体的有效方法。随后,免疫检测可用于区分吸附部分中的 TTR 单体和其他低分子量蛋白质。我们设计了一种两步检测法(ImmunoSieve 检测法),将分子筛分和免疫检测结合起来,以检测单体转甲状腺素。该检测方法用于分析 10 人的血浆微量样本,包括 5 名 TTR-V30M 症前携带者(全球最常见的淀粉样变性 TTR 相关变体)和 5 名健康对照者:结果:ImmunoSieve 检测方法能灵敏地检测血浆微量样本中的单体转甲状腺素。此外,淀粉样变性 TTR 突变携带者的循环中单体 TTR 水平明显更高:结论:TTR单体可作为一种生物标记物,用于评估疾病进展和对稳定原生TTR的疗法的反应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Transthyretin monomers: a new plasma biomarker for pre-symptomatic transthyretin-related amyloidosis.

Background: Genotyping and amyloid fibril detection in tissues are generally considered the diagnostic gold standard in transthyretin-related amyloidosis. Patients carry less stable TTR homotetramers prone to dissociation into non-native monomers, which rapidly self-assemble into oligomers and, ultimately, amyloid fibrils. Thus, the initial event of the amyloid cascade produces the smallest transthyretin species: the monomers. This creates engineering opportunities for diagnosis that remain unexplored.

Methods: We hypothesise that molecular sieving represents a promising method for isolating and concentrating trace TTR monomers from the tetramers present in plasma samples. Subsequently, immunodetection can be utilised to distinguish monomeric TTR from other low molecular weight proteins within the adsorbed fraction. A two-step assay was devised (ImmunoSieve assay), combining molecular sieving and immunodetection for sensing monomeric transthyretin. This assay was employed to analyse plasma microsamples from 10 individuals, including 5 pre-symptomatic carriers of TTR-V30M, the most prevalent amyloidosis-associated TTR variant worldwide, and 5 healthy controls.

Results: The ImmunoSieve assay enable sensitive detection of monomeric transthyretin in plasma microsamples. Moreover, the circulating monomeric TTR levels were significantly higher in carriers of amyloidogenic TTR mutation.

Conclusions: Monomeric TTR can function as a biomarker for evaluating disease progression and assessing responses to therapies targeted at stabilising native TTR.

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来源期刊
Amyloid-Journal of Protein Folding Disorders
Amyloid-Journal of Protein Folding Disorders 生物-生化与分子生物学
CiteScore
10.60
自引率
10.90%
发文量
48
审稿时长
6-12 weeks
期刊介绍: Amyloid: the Journal of Protein Folding Disorders is dedicated to the study of all aspects of the protein groups and associated disorders that are classified as the amyloidoses as well as other disorders associated with abnormal protein folding. The journals major focus points are: etiology, pathogenesis, histopathology, chemical structure, nature of fibrillogenesis; whilst also publishing papers on the basic and chemical genetic aspects of many of these disorders. Amyloid is recognised as one of the leading publications on amyloid protein classifications and the associated disorders, as well as clinical studies on all aspects of amyloid related neurodegenerative diseases and major clinical studies on inherited amyloidosis, especially those related to transthyretin. The Journal also publishes book reviews, meeting reports, editorials, thesis abstracts, review articles and symposia in the various areas listed above.
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