Quantitative proteome profiling provides evidence of an activation of the complement cascade in ATTR amyloidosis

Amyloidosis is a disease group caused by pathological aggregation and deposition of peptides in diverse tissue sites. Apart from the fibril protein, amyloid deposits frequently enclose non-fibrillar constituents. In this study, carpal tunnel tissue sections with ATTR amyloid were analysed by quantitative mass spectrometry-based proteomics. Following manual dissection, tissue samples of equal size and with heterogeneous amyloid load were dissected and forwarded to bottom-up proteome analysis and label-free protein profiling. The amyloid-associated proteins showed significant correlations of label-free intensity profiles. A comprehensive list of 83 proteins specifically enriched in amyloid deposits was discovered. In addition to well-known signature proteins (e.g. apolipoprotein E, apolipoprotein A-IV, and vitronectin), 22 members of the complement system, including all seven components of the membrane attack complex could be associated to the disease. These data lend support to the hypothesis that the complement system is activated in ATTR amyloidosis.

淀粉样变性（Amyloidosis）是一类由多肽在多种组织部位发生病理性聚集并沉积所引发的疾病群组。除原纤维蛋白外，淀粉样沉积物通常还包裹有非纤维状组分。本研究采用基于定量质谱的蛋白质组学方法，对携带ATTR淀粉样蛋白的腕管组织切片进行了分析。经手动解剖分离后，我们切取尺寸均一且淀粉样蛋白负载量存在异质性的组织样本，开展自下而上蛋白质组学分析与无标记蛋白质定量谱分析。结果显示，淀粉样蛋白相关蛋白的无标记强度谱呈现出显著相关性。本研究共鉴定出83种在淀粉样沉积物中特异性富集的蛋白质。除载脂蛋白E、载脂蛋白A-IV、玻连蛋白等经典特征蛋白外，补体系统的22种成员（包括膜攻击复合物的全部7种组分）也被证实与该疾病存在关联。上述数据为"补体系统在ATTR淀粉样变性中被激活"这一假说提供了有力支持。