Pathogenesis of transthyretin amyloidosis
Pathogenesis of transthyretin amyloidosis
复制标题
DOI：
10.3109/13506129.2012.668501
复制
发表时间：
2012-06-01
影响因子：
5.5
通讯作者：
Benson, Merrill D.
中科院分区：
文献类型：
--
作者：
Benson, Merrill D.
甲状腺素运载蛋白（TTR）发病机理的当前教条是TTR中的突变改变其结构，使得四聚体变得不稳定并且倾向于释放单体，所述单体然后成为原纤维的推定构建单元。这一假设得到了热力学数据的支持，这些数据显示突变TTR四聚体蛋白在体外酸性条件下的稳定性降低和原纤维形成加速。然而，对于一种非常复杂的疾病，这种简单化的模型还不能轻易回答许多问题。有待回答的问题包括：1。如果单体是原纤维的前体，为什么原纤维沉积物含有大量的野生型TTR而不仅仅是变体？2.如果不稳定的四聚体可以在体外形成原纤维，为什么我们总是发现原纤维亚基蛋白的部分蛋白水解？如果酶促蛋白水解是原纤维形成的必要步骤，那么体外原纤维形成的发现是否与真正的发病机制有关？3.对于一些TTR突变（例如122 Δ瓦尔），血液中似乎存在非常少的TTR（可能是由于肝分泌前的降解）。足够的突变TTR循环到心脏和神经引起病理，但是，如果突变只用于启动原纤维沉积，为什么沉积物主要不是野生型TTR？4.既然TTR突变从出生就存在，为什么TTR淀粉样变性会延迟发病？衰老因素的作用是什么？5.心脏和神经与脉络膜和软脑膜纤维的生化分析的变化是否告诉我们一些关于发病机制的信息？这些都是我们需要解决的问题。不要期待快速和简单的答案。希望他们能引起思考和讨论。
Current dogma for transthyretin (TTR) pathogenesis is that mutations in TTR alter its structure such that the tetramer becomes unstable and prone to release of monomer which then becomes the putative building block of the fibril. This hypothesis is supported by thermodynamic data showing decreased stability of mutant TTR tetrameric proteins and accelerated fibril formation under acidic conditions in vitro. There are, however, a number of questions that are not readily answered by this simplistic model of a very complex disease. Worrisome questions still to be answered include: 1. If the monomer is the precursor of the fibril, why do fibril deposits contain large amounts of wild-type TTR and not just variant? 2. If destabilized tetramers can form fibrils in vitro, why do we consistently find partial proteolysis of fibril subunit proteins? If enzymatic proteolysis is a required step in fibril formation, are the findings of in vitro fibril formation relevant to the true pathogenesis? 3. With some TTR mutations (e.g. 122 Delta Val), it would appear that very little TTR is present in the blood (probably due to degradation prior to hepatic secretion). Enough mutant TTR circulates to the heart and nerves to cause pathology but, if the mutant only serves to initiate fibril deposition, why are not the deposits mainly wild-type TTR? 4. Since mutated TTR is present from birth, why is TTR amyloidosis of such delayed onset? What is the role of aging factors? 5. Do the variations in biochemical analyses of heart and nerve versus choroid and leptomeningeal fibrils tell us something about pathogenesis? These are questions we need to address. Do not expect quick and easy answers. Hopefully, they will generate thought and discussion.