Pathogenesis, diagnosis and treatment of systemic amyloidosis
Pathogenesis, diagnosis and treatment of systemic amyloidosis
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DOI：
10.1098/rstb.2000.0766
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发表时间：
2001-02-28
影响因子：
6.3
通讯作者：
Pepys, MB
中科院分区：
文献类型：
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作者：
Pepys, MB
淀粉样变性是一种蛋白质折叠疾病，其中通常可溶的蛋白质沉积为异常的不溶性原纤维，破坏组织结构并引起疾病。尽管大约 20 种不同的不相关蛋白质可以在体内形成淀粉样原纤维，但所有此类原纤维都具有共同的交叉 β 核心结构。一些天然野生型蛋白质本质上是淀粉样变性的，形成原纤维并在老年时或如果长时间以异常高浓度存在则引起淀粉样变性。其他淀粉样蛋白是获得性或遗传性变体，含有使它们不稳定的氨基酸取代，因此它们在生理条件下处于部分未折叠状态，然后这些中间体聚集在稳定的淀粉样蛋白折叠中。除原纤维外，淀粉样蛋白沉积物始终含有非原纤维五聚蛋白血浆蛋白、血清淀粉样蛋白 P 成分 (SAP)，因为它与淀粉样蛋白原纤维进行特定的钙依赖性结合。 SAP 可能通过稳定淀粉样原纤维并延缓其清除而促进淀粉样蛋白生成。放射性标记 SAP 是一种极其有用、安全、特异、非侵入性的定量示踪剂，用于全身淀粉样沉积物的闪烁显像。它的使用已经证明，消除淀粉样原纤维前体蛋白的供应可以导致淀粉样蛋白沉积物的消退，从而具有临床益处。目前淀粉样变性的治疗包括仔细维持受损的器官功能，通过透析或移植替代终末期器官衰竭，以及大力控制导致原纤维前体产生的潜在病症。正在开发的新方法包括用于稳定前体蛋白天然折叠的药物、抑制原纤维形成、使淀粉样蛋白回复到天然折叠以及解离SAP以加速体内淀粉样蛋白原纤维清除。
Amyloidosis is a disorder of protein folding in which normally soluble proteins are deposited as abnormal, insoluble fibrils that disrupt tissue structure and cause disease. Although about 20 different unrelated proteins can form amyloid fibrils in vivo, all such fibrils share a common cross-beta core structure. Some natural wild-type proteins are inherently amyloidogenic, form fibrils and cause amyloidosis in old age or if present for long periods at abnormally high concentration. Other amyloidogenic proteins are acquired or inherited variants, containing amino-acid substitutions that render them unstable so that they populate partly unfolded states under physiological conditions, and these intermediates then aggregate in the stable amyloid fold. In addition to the fibrils, amyloid deposits always contain the non-fibrillar pentraxin plasma protein, serum amyloid P component (SAP), because it undergoes specific calcium-dependent binding to amyloid fibrils. SAP contributes to amyloidogeneses, probably by stabilizing amyloid fibrils and retarding their clearance. Radiolabelled SAP is an extremely useful, safe, specific, non-invasive, quantitative tracer for scintigraphic imaging of systemic amyloid deposits. Its use has demonstrated that elimination of the supply of amyloid fibril precursor proteins leads to regression of amyloid deposits with clinical benefit. Current treatment of amyloidosis comprises careful maintenance of impaired organ function, replacement of end-stage organ failure by dialysis or transplantation, and vigorous efforts to control underlying conditions responsible for production of fibril precursors. New approaches under development include drugs for stabilization of the native fold of precursor proteins, inhibition of fibrillogenesis, reversion of the amyloid to the native fold, and dissociation of SAP to accelerate amyloid fibril clearance in vivo.