{"title":"Multistep growth of amyloid intermediates and its inhibition toward exploring therapeutic way: A case study using insulin B chain and fibrinogen.","authors":"Naoki Yamamoto, Eri Chatani","doi":"10.2142/biophysico.bppb-v19.0017","DOIUrl":null,"url":null,"abstract":"<p><p>It is crucial to understand the mechanism of amyloid fibril formation for the development of the therapeutic ways against amyloidoses and neurodegenerative diseases. Prefibrillar intermediates, which emerge prior to the fibril formation, seem to play a key role to the occurrence of nuclei of amyloid fibrils. We have focused on an insulin-derived peptide, B chain, to precisely clarify the mechanism of the fibril formation via prefibrillar intermediates. Various kinds of methods such as circular dichroism spectroscopy, dynamic light scattering, small-angle X-ray scattering, and atomic force microscopy were employed to track the structural changes in prefibrillar intermediates. The prefibrillar intermediates possessing rod-shaped structures elongated as a function of time, which led to fibril formation. We have also found that a blood clotting protein, fibrinogen, inhibits the amyloid fibril formation of B chain. This was caused by the stabilization of prefibrillar intermediates and thus the suppression of their elongation by fibrinogen. These findings have not only shed light on detailed mechanisms about how prefibrillar intermediates convert to the amyloid fibril, but also demonstrated that inhibiting the structural development of prefibrillar intermediates is an effective strategy to develop therapeutic ways against amyloid-related diseases. This review article is an extended version of the Japanese article, Observing Development of Amyloid Prefibrillar Intermediates and their Interaction with Chaperones for Inhibiting the Fibril Formation, published in SEIBUTSU BUTSURI Vol. 61, p. 236-239 (2021).</p>","PeriodicalId":8976,"journal":{"name":"Biophysics and Physicobiology","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2022-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/4e/5b/19_e190017.PMC9173859.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biophysics and Physicobiology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.2142/biophysico.bppb-v19.0017","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2022/1/1 0:00:00","PubModel":"eCollection","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
It is crucial to understand the mechanism of amyloid fibril formation for the development of the therapeutic ways against amyloidoses and neurodegenerative diseases. Prefibrillar intermediates, which emerge prior to the fibril formation, seem to play a key role to the occurrence of nuclei of amyloid fibrils. We have focused on an insulin-derived peptide, B chain, to precisely clarify the mechanism of the fibril formation via prefibrillar intermediates. Various kinds of methods such as circular dichroism spectroscopy, dynamic light scattering, small-angle X-ray scattering, and atomic force microscopy were employed to track the structural changes in prefibrillar intermediates. The prefibrillar intermediates possessing rod-shaped structures elongated as a function of time, which led to fibril formation. We have also found that a blood clotting protein, fibrinogen, inhibits the amyloid fibril formation of B chain. This was caused by the stabilization of prefibrillar intermediates and thus the suppression of their elongation by fibrinogen. These findings have not only shed light on detailed mechanisms about how prefibrillar intermediates convert to the amyloid fibril, but also demonstrated that inhibiting the structural development of prefibrillar intermediates is an effective strategy to develop therapeutic ways against amyloid-related diseases. This review article is an extended version of the Japanese article, Observing Development of Amyloid Prefibrillar Intermediates and their Interaction with Chaperones for Inhibiting the Fibril Formation, published in SEIBUTSU BUTSURI Vol. 61, p. 236-239 (2021).
了解淀粉样蛋白纤维的形成机制对于开发治疗淀粉样蛋白病和神经退行性疾病的方法至关重要。在纤维形成之前出现的前纤维中间体似乎对淀粉样纤维核的出现起着关键作用。我们以胰岛素衍生肽 B 链为研究对象,旨在精确阐明淀粉样蛋白纤维通过前纤维中间体形成的机制。我们采用了圆二色性光谱、动态光散射、小角 X 射线散射和原子力显微镜等多种方法来追踪前纤维素中间体的结构变化。具有杆状结构的前纤维中间体随着时间的推移而伸长,从而形成纤维。我们还发现,凝血蛋白纤维蛋白原能抑制 B 链淀粉样纤维的形成。这是因为纤维蛋白原稳定了纤维前中间体,从而抑制了它们的伸长。这些发现不仅揭示了前纤维中间产物如何转化为淀粉样纤维的详细机制,还证明了抑制前纤维中间产物的结构发展是开发淀粉样相关疾病治疗方法的有效策略。本综述文章是日文文章《观察淀粉样蛋白纤前中间体的发展及其与伴侣蛋白的相互作用以抑制纤维的形成》(Observing Development of Amyloid Prefibrillar Intermediates and their Interaction with Chaperones for Inhibiting the Fibril Formation)的扩展版,发表于《科学文摘》(SEIBUTSU BUTSURI)第61卷第236-239页(2021年)。