Cryo-EM structures of AL amyloid fibrils from human heart

AL淀粉样纤维是系统性AL淀粉样变性的关键致病因子。它们在不同的患者之间形态可变，但对其确切结构知之甚少。例如，至今仍不清楚心脏淀粉样变性的不同病例是否涉及纤维蛋白的相似折叠构象或错误折叠状态。使用从具有强烈心脏受累的患者的心脏破裂的心脏提取的AL淀粉样蛋白原纤维，我们将解决以下目的：（i）从心脏淀粉样蛋白沉积物提取λ-AL淀粉样蛋白原纤维。(ii)确定患者源性AL淀粉样蛋白原纤维的冷冻电子显微镜结构。(iii)确定λ-AL淀粉样纤维的结构多样性。(iv)比较AL淀粉样纤维与轻链衍生的淀粉样纤维。通过这项工作，我们将测试的假设，在心脏AL淀粉样变性的原纤维形成涉及共同的结构主题的大会在体内。我们的工作主要是为了促进对系统性AL淀粉样变性的分子机制、AL淀粉样纤维的结构特征及其变异性的更好理解。此外，它将帮助我们进一步阐明原纤维形成的机制，因为它发生在患者体内的自然条件下。

AL amyloid fibrils are key pathogenic agents in systemic AL amyloidosis. They are morphologically variable between different patients but little is known about their exact structures. For example, it is so far remained unclear whether different cases of cardiac amyloidosis involve similarly folded conformations or misfolded states of the fibril protein. Using AL amyloid fibril extracted from the explanted hearts of patients with a strong cardiac involvement we will address the following aims: (i) To extract Lambda-AL amyloid fibrils from cardiac amyloid deposits. (ii) To determine the cryo electron microscopy structure of a patient-derived AL amyloid fibril. (iii) To determine the structural diversity of Lambda-AL amyloid fibrils. (iv) To compare AL amyloid fibrils with light chain-derived amyloid-like fibrils. Through this work we will test the hypothesis that fibril formation in cardiac AL amyloidosis involves common structural themes for the assembly in vivo. Our work intends primarily to promote a better understanding of the molecular agents underlying systemic AL amyloidosis, the structural specifics of AL amyloid fibrils and their variability. Moreover, it will help us to further clarify the mechanism of fibril formation as it occur under natural conditions inside a patient.