Dynamic changes of intracellular signals in ATTR Tyr114Cys amyloidosis

IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemistry and Biophysics Reports Pub Date : 2025-04-15 DOI:10.1016/j.bbrep.2025.102012

Kenta Ouchi , Takeshi Masuda , Kou Yonemaru , Kaori Isono , Yuki Ohya , Nobuaki Shiraki , Masayoshi Tasaki , Yukihiro Inomata , Mitsuharu Ueda , Takumi Era , Shoen Kume , Yukio Ando , Hirofumi Jono

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引用次数: 0

Abstract

Hereditary transthyretin (TTR) amyloidosis (ATTRv amyloidosis) is an autosomal dominant disease caused by various TTR mutations. Despite the fact that ATTR Tyr114Cys (p.Tyr134Cys) amyloidosis (tyrosine to cysteine at codon 114) exhibits poorer prognosis than other ATTRv amyloidosis and leads to death due to severe clinical symptoms, the molecular pathogenesis of ATTR Tyr114Cys amyloidosis is still largely unknown. In this study, we took advantage of ATTR Tyr114Cys amyloidosis-specific induced pluripotent stem (iPS) cells to differentiate into hepatocyte-like cells (Y114C-HLCs), which are mainly TTR producing cells, and elucidated their pathogenesis. We performed proteomic analysis to comprehensively identify specific intracellular signaling pathways involved in Y114C-HLCs, and identified the specific proteins changed only in Y114C-HLCs, in comparison with disease control HLCs from ATTR Val30Met amyloidosis (V30M-HLCs). Moreover, we have succeeded in identifying several specific intracellular signals that are significantly activated in Y114C-HLCs, including cellular responses to stress and extracellular matrix organization. Our proteomic analysis is the first to report that the specific point mutations in ATTRv amyloidosis cause dynamic changes in cellular response, and reveal the specific intracellular signals may be involved in the specific pathogenesis of ATTR Tyr114Cys amyloidosis.

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ATTR Tyr114Cys淀粉样变中细胞内信号的动态变化

遗传性转甲状腺素（TTR）淀粉样变性病（ATTRv amyloidosis，ATTRv淀粉样变性病）是一种由各种TTR突变引起的常染色体显性遗传病。尽管与其他 ATTRv 淀粉样变性相比，ATTR Tyr114Cys（p.Tyr134Cys）淀粉样变性（密码子 114 上的酪氨酸变半胱氨酸）的预后较差，并会因严重的临床症状而导致死亡，但 ATTR Tyr114Cys 淀粉样变性的分子发病机制在很大程度上仍是未知的。在本研究中，我们利用ATTR Tyr114Cys淀粉样变性特异性诱导多能干细胞（iPS）分化成肝细胞样细胞（Y114C-HLCs），该细胞主要是产生TTR的细胞，并阐明了其发病机制。我们进行了蛋白质组学分析，全面鉴定了参与Y114C-HLCs的特定细胞内信号通路，并与来自ATTR Val30Met淀粉样变性的疾病对照HLCs（V30M-HLCs）相比，鉴定了仅在Y114C-HLCs中发生变化的特定蛋白质。此外，我们还成功鉴定了在Y114C-HLCs中被显著激活的几种特定细胞内信号，包括细胞对应激的反应和细胞外基质组织。我们的蛋白质组分析首次报道了ATTRv淀粉样变性中的特定点突变会引起细胞反应的动态变化，并揭示了特定的细胞内信号可能参与了ATTR Tyr114Cys淀粉样变性的特定发病机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochemistry and Biophysics Reports Biochemistry, Genetics and Molecular Biology-Biophysics

CiteScore

4.60

自引率

0.00%

发文量

191

审稿时长

59 days

期刊介绍： Open access, online only, peer-reviewed international journal in the Life Sciences, established in 2014 Biochemistry and Biophysics Reports (BB Reports) publishes original research in all aspects of Biochemistry, Biophysics and related areas like Molecular and Cell Biology. BB Reports welcomes solid though more preliminary, descriptive and small scale results if they have the potential to stimulate and/or contribute to future research, leading to new insights or hypothesis. Primary criteria for acceptance is that the work is original, scientifically and technically sound and provides valuable knowledge to life sciences research. We strongly believe all results deserve to be published and documented for the advancement of science. BB Reports specifically appreciates receiving reports on: Negative results, Replication studies, Reanalysis of previous datasets.