Benson M D, Kluve-Beckerman B, Liepnieks J J, Murrell J R, Hanes D, Uemichi T
Indiana University School of Medicine, Department of Medicine, Indianapolis, USA.
Ciba Found Symp. 1996;199:104-13; discussion 113-8. doi: 10.1002/9780470514924.ch7.
Metabolic processing of amyloid precursor proteins is an important factor in the genesis of practically all forms of amyloidosis. Of the three major forms of systemic amyloidosis, reactive amyloid (amyloid A protein; AA) formation shows the most consistent role of partial proteolysis of serum amyloid A (SAA) to AA proteins which form fibrils. Immunoglobulin amyloidosis is also usually associated with C-terminal degradation of the fibril precursor light chain protein. Although it is commonly thought that transthyretin amyloidosis is associated with fibril formation from the tetrameric circulating plasma transthyretin, chemical analyses of transthyretin fibril deposits show significant fragmentation of the fibril protein constituents. In addition, it has been documented that proteolytic fragments are the fibril subunit proteins in gelsolin, cystatin C. Alzheimer's beta-amyloid precursor protein and apolipoprotein AI (apoAI) amyloidoses. Notable exceptions to the role of proteolysis in amyloid fibril formation would appear to be the lysozyme and beta 2-microglobulin amyloidoses. Few studies have examined the metabolism of amyloid-forming proteins. Perhaps the best data are on apoAI, which show decreased plasma residence time for the amyloidogenic Gly26Arg apoAI (1.8 d vs. normal 4.5 d). Similarly, preliminary data show increased clearance of Val30Met transthyretin when compared with the wild-type protein (18 h vs. 26 h). Also, biosynthetically 35S-labelled SAA proteins reconstituted with HDL show increased plasma clearance of murine SAA2, the amyloid fibril subunit protein, when compared with murine SAA1. Few data are available on metabolism of amyloid immunoglobulin light chain proteins, but it has been shown that radiolabelled Bence-Jones proteins are cleared very rapidly from the circulation. A better understanding of the metabolism of precursor proteins in each of the amyloid deposition diseases will give insight into the mechanisms of fibril formation and pathogenesis of amyloidosis.
淀粉样前体蛋白的代谢过程是几乎所有形式淀粉样变性发生的一个重要因素。在三种主要的系统性淀粉样变性中，反应性淀粉样变性（淀粉样A蛋白；AA）的形成显示出血清淀粉样A（SAA）部分蛋白水解为形成纤维的AA蛋白的最一致作用。免疫球蛋白淀粉样变性通常也与纤维前体轻链蛋白的C末端降解有关。尽管通常认为转甲状腺素蛋白淀粉样变性与循环血浆中转甲状腺素蛋白四聚体形成纤维有关，但对转甲状腺素蛋白纤维沉积物的化学分析显示纤维蛋白成分有显著片段化。此外，有文献记载蛋白水解片段是凝溶胶蛋白、胱抑素C、阿尔茨海默病β淀粉样前体蛋白和载脂蛋白AI（apoAI）淀粉样变性中的纤维亚基蛋白。蛋白水解在淀粉样纤维形成中的作用的显著例外似乎是溶菌酶和β2微球蛋白淀粉样变性。很少有研究考察形成淀粉样蛋白的蛋白质的代谢。也许关于apoAI的最佳数据显示，致淀粉样变性的Gly26Arg apoAI的血浆停留时间缩短（1.8天对正常的4.5天）。同样，初步数据显示，与野生型蛋白相比，Val30Met转甲状腺素蛋白的清除率增加（18小时对26小时）。此外，与小鼠SAA1相比，用高密度脂蛋白重构的生物合成35S标记的SAA蛋白显示小鼠SAA2（淀粉样纤维亚基蛋白）的血浆清除率增加。关于淀粉样免疫球蛋白轻链蛋白的代谢数据很少，但已表明放射性标记的本周氏蛋白从循环中清除非常迅速。更好地了解每种淀粉样沉积疾病中前体蛋白的代谢将有助于深入了解淀粉样变性的纤维形成机制和发病机制。
