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在形态上是不同的，但对它们的确切结构知之甚少。例如，到目前为止，尚不清楚不同的心脏淀粉样变性病例是否涉及类似的折叠构象或纤维蛋白的错误折叠状态。使用从心脏受累程度较高的患者的移植心脏中提取的AL淀粉样纤维，我们将解决以下目标：(I)从心脏淀粉样沉积中提取Lambda-AL淀粉样纤维。(Ii)确定患者来源的AL淀粉样原纤维的冷冻电子显微镜结构。(Iii)测定Lambda-AL淀粉样纤维的结构多样性。(4)比较AL淀粉样原纤维与轻链淀粉样原纤维。通过这项工作，我们将检验这一假设，即心脏AL淀粉样变性中的纤维形成涉及体内组装的共同结构主题。我们的工作主要是为了促进更好地了解系统性AL淀粉样变性的分子机制、AL淀粉样纤维的结构特点及其变异性。此外，这将有助于我们进一步阐明在患者体内自然条件下纤维形成的机制。

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.