了解淀粉样蛋白原纤维形成的机制对于开发针对淀粉样变和神经退行性疾病的治疗方法至关重要。原纤中间体,在原纤维形成之前出现,似乎对淀粉样纤维核的发生起着关键作用。我们专注于胰岛素衍生肽,B链,以精确阐明通过原纤中间体形成原纤维的机理。各种方法,如圆二色光谱,动态光散射,小角度X射线散射,和原子力显微镜用于跟踪原纤中间体的结构变化。具有杆状结构的前原纤中间体随时间延长,这导致了原纤维的形成。我们还发现了一种血液凝固蛋白,纤维蛋白原,抑制B链的淀粉样蛋白原纤维形成。这是由前纤丝中间体的稳定以及纤维蛋白原对其伸长的抑制引起的。这些发现不仅揭示了纤丝前中间体如何转化为淀粉样纤维的详细机制,但也证明抑制原纤维中间体的结构发育是开发针对淀粉样蛋白相关疾病的治疗方法的有效策略。这篇评论文章是日本文章的扩展版本,观察淀粉样前纤丝中间体的发育及其与伴侣的相互作用以抑制纤维形成,发表在SEIBUTSUBUTSURI卷。61,第236-239页(2021年)。
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).