D18G transthyretin is monomeric, aggregation prone, and not detectable in plasma and cerebrospinal fluid:: A prescription for central nervous system amyloidosis?
D18G transthyretin is monomeric, aggregation prone, and not detectable in plasma and cerebrospinal fluid:: A prescription for central nervous system amyloidosis?
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DOI：
10.1021/bi027319b
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发表时间：
2003-06-10
期刊：
影响因子：
2.9
通讯作者：
Kelly, JW
中科院分区：
文献类型：
--
作者：
Hammarström, P;Sekijima, Y;Kelly, JW
超过70个转甲状腺素(TTR)突变促进了中枢神经系统(CNS)以外组织中的淀粉样变性。相比之下，匈牙利人后裔中的D18G TTR突变会导致中枢神经系统淀粉样变性。D18G在大肠杆菌中形成包涵体，不同于迄今为止过度表达的其他与疾病相关的TTR变异体。D18G从包涵体中变性和重组得到的折叠单体相对于工程单体WT TTR的不稳定程度为3.1kcal/mol。由于TTR四聚体的解离对于淀粉样蛋白的形成是典型的速率限制，D18G的单体性质使其淀粉样蛋白的形成速度比WT快1000倍。令人困惑的是，D18G并没有导致严重的早发性系统性淀粉样变性，因为它是迄今为止最不稳定的TTR变异体，比第二个十年表现出的变异体更不稳定。相反，中枢神经系统损害在第五个十年中被观察到是唯一的病理表现；然而，也观察到良性的全身沉积。对杂合子D18G患者血清和脑脊液(CSF)的分析仅检测到WT TTR，表明D18G要么在分泌后迅速降解，要么在分泌前在细胞内降解，这与其无法与WT TTR形成杂交四聚体一致。人类血浆中无法检测到的D18G TTR水平解释了没有早发性全身性疾病。中枢神经系统疾病可能是由于中枢神经系统对低水平的D18G聚集体的敏感性所致。或者，或者另外，我们推测脉络丛产生的一部分D18G可以被局部高浓度的甲状腺素(T-4)瞬时四聚，伴随着它进入脑脊液，在那里由于T4CSF浓度低，它经历了解离和淀粉样变。选定的小分子四聚体稳定剂可以将D18G从单体聚集倾向状态转变为非淀粉样变性四聚体，这可能被证明是一种有用的治疗策略，可用于治疗TTR相关的中枢神经系统淀粉样变性。
Over 70 transthyretin (TTR) mutations facilitate amyloidosis in tissues other than the central nervous system (CNS). In contrast, the D18G TTR mutation in individuals of Hungarian descent leads to CNS amyloidosis. D18G forms inclusion bodies in Escherichia coli, unlike the other disease-associated TTR variants overexpressed to date. Denaturation and reconstitution of D18G from inclusion bodies afford a folded monomer that is destabilized by 3.1 kcal/mol relative to an engineered monomeric version of WT TTR. Since TTR tetramer dissociation is typically rate limiting for amyloid formation, the monomeric nature of D18G renders its amyloid formation rate 1000-fold faster than WT. It is perplexing that D18G does not lead to severe early onset systemic amyloidosis, given that it is the most destabilized TTR variant characterized to date, more so than variants exhibiting onset in the second decade. Instead, CNS impairment is observed in the fifth decade as the sole pathological manifestation; however, benign systemic deposition is also observed. Analysis of heterozygote D18G patient's serum and cerebrospinal fluid (CSF) detects only WT TTR, indicating that D18G is either rapidly degraded postsecretion or degraded within the cell prior to secretion, consistent with its inability to form hybrid tetramers with WT TTR. The nondetectable levels of D18G TTR in human plasma explain the absence of an early onset systemic disease. CNS disease may result owing to the sensitivity of the CNS to lower levels of D18G aggregate. Alternatively, or in addition, we speculate that a fraction of D18G made by the choroid plexus can be transiently tetramerized by the locally high thyroxine (T-4) concentration, chaperoning it out into the CSF where it undergoes dissociation and amyloidogenesis due to the low T4CSF concentration. Selected small molecule tetramer stabilizers can transform D18G from a monomeric aggregation-prone state to a nonamyloidogenic tetramer, which may prove to be a useful therapeutic strategy against TTR-associated CNS amyloidosis.