Presence of N-glycosylated transthyretin in plasma of V30M carriers in familial amyloidotic polyneuropathy: an escape from ERAD.
Presence of N-glycosylated transthyretin in plasma of V30M carriers in familial amyloidotic polyneuropathy: an escape from ERAD.
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DOI：
10.1111/jcmm.12024
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发表时间：
2013-03
影响因子：
5.3
通讯作者：
Saraiva MJ
中科院分区：
文献类型：
--
作者：
Teixeira AC;Saraiva MJ
家族性淀粉样蛋白多发性神经病（FAP）是一种常染色体显性遗传病，其特征是淀粉样蛋白沉积与转甲状腺素（TTR）基因突变有关。TTR主要在肝脏、脑脉络膜丛和胰腺中合成，并分泌到血浆和脑脊液中。虽然它在第98位具有n -糖基化N-D-S序列，但它不是作为糖蛋白分泌的。最常见的与fap相关的突变是TTR V30M。在筛选针对淀粉样变性TTR形式的单克隆抗体时，我们在V30M突变携带者的西部血浆中检测到一种明显的TTR，其电泳迁移率较慢，而在正常血浆中不存在。对这种迁移速度较慢的TTR （SMT）进行质谱分析，鉴定出野生型和突变型V30M；在n -糖苷酶F处理下，SMT检测不到。此外，肝移植后V30M - FAP患者血浆中的SMT很快消失，而接受V30M肝移植的多米诺骨牌个体血浆中出现SMT。人V30M突变转基因小鼠的血浆中也检测到SMT，但脑脊液中未检测到SMT。转染表达人V30M的肝癌细胞系在分泌介质中未出现SMT修饰。从人肾V30M解剖组织中提取的原纤维或从人TTR转基因小鼠的肠道中提取的TTR聚集体中不存在糖基化的TTR。研究这种从FAP肝脏分泌的新型糖基化TTR的代谢，有必要为蛋白质质量控制和疾病的发病机制提供新的机制。
Familial amyloid polyneuropathy (FAP) is an autosomal dominant disease characterized by deposition of amyloid related to the presence of mutations in the transthyretin (TTR) gene. TTR is mainly synthesized in liver, choroid plexuses of brain and pancreas and secreted to plasma and cerebrospinal fluid (CSF). Although it possesses a sequon for N-glycosylation N-D-S at position 98, it is not secreted as a glycoprotein. The most common FAP-associated mutation is TTR V30M. In a screening for monoclonal antibodies developed against an amyloidogenic TTR form, we detected a distinct TTR with slower electrophoretic mobility in Western of plasma from carriers of the V30M mutation, not present in normal plasma. Mass spectrometry analyses of this slower migrating TTR (SMT) identified both wild-type and mutant V30M; SMT was undetectable upon N-glycosidase F treatment. Furthermore, SMT readily disappeared in the plasma of V30M - FAP patients after liver transplantation and appeared in plasma of transplanted domino individuals that received a V30M liver. SMT was also detected in plasma, but not in CSF of transgenic mice for the human V30M mutation. A hepatoma cell line transduced to express human V30M did not present the SMT modification in secretion media. Glycosylated TTR was absent in fibrils extracted from human kidney V30M autopsy tissue or in TTR aggregates extracted from the intestine of human TTR transgenic mice. Studies on the metabolism of this novel, glycosylated TTR secreted from FAP liver are warranted to provide new mechanisms in protein quality control and etiopathogenesis of the disease.
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影响因子：
4.3
作者：
Bolt, G;Kristensen, C;Steenstrup, TD
通讯作者：
Steenstrup, TD
影响因子：
4.4
作者：
Yamashita, T;Ando, Y;Ando, M
通讯作者：
Ando, M
DOI：
10.1073/pnas.96.6.3108
发表时间：
1999-03-16
影响因子：
11.1
作者：
Goldsteins, G;Persson, H;Lundgren, E
通讯作者：
Lundgren, E
影响因子：
4.8
作者：
Sousa, MM;Saraiva, MJ
通讯作者：
Saraiva, MJ
影响因子：
4.7
作者：
Palha, JA;Moreira, P;Saraiva, MJ
通讯作者：
Saraiva, MJ