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首页> 外文期刊>The FEBS journal >The aggregation potential of human amylin determines its cytotoxicity towards islet beta-cells
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The aggregation potential of human amylin determines its cytotoxicity towards islet beta-cells

机译：人胰岛淀粉样多肽的聚集潜力决定了其对胰岛β细胞的细胞毒性

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摘要

Human amylin is a small fibrillogenic protein that is the major constituent of pancreatic islet amyloid, which occurs in most subjects with type 2 diabetes. There is evidence that it can elicit in vitro apoptosis in islet beta-cells, but the physical properties that underpin its cytotoxicity have not been clearly elucidated. Here we employed electron microscopy, thioflavin T fluorescence and CD spectroscopy to analyze amylin preparations whose cytotoxic potential was established by live-dead assay in cultured beta-cells. Highly toxic amylin contained few preformed fibrils and initially showed little beta-sheet content, but underwent marked time-dependent aggregation and beta-conformer formation following dissolution. By contrast, low-toxicity amylin contained abundant preformed fibrils, and demonstrated high initial beta-sheet content but little propensity to aggregate further once dissolved. Thus, mature amylin fibrils are not toxic to beta-cells, and aggregates of fibrils such as occur in pancreatic islet amyloid in vivo are unlikely to contribute to beta-cell loss. Rather, the toxic molecular species is likely to comprise soluble oligomers with significant beta-sheet content. Attempts to find ways of protecting beta-cells from amylin-mediated death might profitably focus on preventing the conformational change from random coil to beta-sheet.
机译：人胰岛淀粉样多肽是一种小的原纤维蛋白，是胰岛淀粉样淀粉样蛋白的主要成分，在大多数2型糖尿病患者中都存在。有证据表明它可以引起胰岛β细胞的体外凋亡，但是尚不清楚其细胞毒性的物理性质。在这里，我们使用电子显微镜，硫黄素T荧光和CD光谱分析了胰岛淀粉样多肽制剂，其通过活死法在培养的β细胞中建立了细胞毒性潜力。剧毒的胰岛淀粉样多肽含有很少的预制纤维，最初显示很少的β-折叠含量，但是溶解后经历了明显的时间依赖性聚集和β-构象异构体形成。相比之下，低毒性胰岛淀粉样多肽含有丰富的预制原纤维，并显示出较高的初始β-折叠含量，但一旦溶解后几乎没有进一步聚集的倾向。因此，成熟的胰岛淀粉样多肽原纤维对β细胞没有毒性，并且诸如在体内胰岛淀粉样蛋白中发生的原纤维聚集体不太可能导致β细胞丢失。而是，毒性分子物质可能包含具有显着β-折叠含量的可溶性低聚物。试图找到保护β细胞免受胰岛淀粉样多肽介导的死亡的方法的尝试可能有益地集中在防止从无规卷曲到β-折叠的构象变化。

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