Presenilin-1 mutations associated with familial Alzheimer's disease do not disrupt protein transport from the endoplasmic reticulum to the Golgi apparatus.
Presenilin-1 mutations associated with familial Alzheimer's disease do not disrupt protein transport from the endoplasmic reticulum to the Golgi apparatus.
复制标题
与家族性阿尔茨海默病相关的早老素-1 突变不会破坏蛋白质从内质网到高尔基体的转运。
DOI：
10.1016/s0925-4439(98)00031-3
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Maltese,WA
中科院分区：
文献类型：
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作者：
Tan,Y;Hong,J;Doan,T;McConlogue,L;Maltese,WA
编码早老素-1（PS1）和早老素-2（PS2）的基因突变与家族性阿尔茨海默病（AD）有关。表达突变早老素的细胞产生升高水平的Aβ42，A β 42是AD斑块中发现的主要淀粉样肽。其发生的机制尚不清楚，但早老蛋白定位于内质网（ER）和高尔基体区室表明，它们可能在参与加工β-淀粉样前体蛋白（APP）的细胞内运输途径中发挥作用。为了测试这种可能性，我们在HEK 293细胞中共表达PS1（wt）、PS1（M146 L）或PS1（L286 V）以及LDL受体，LDL受体是一种经典的糖蛋白标记物，在高尔基体中经历翻译后O-糖基化。受体的脉冲追踪分析表明，突变早老素对ER→高尔基体转运没有影响。当用表达APP的瑞典变体（SWAPP 751）而不是LDL受体的细胞进行研究时，获得了类似的结果。此外，由α-分泌酶和β-分泌酶切割产生的SWAPP 751的可溶性胞外结构域多肽片段的分泌不受PS1突变体的显著影响。尽管PS1突变体对蛋白质通过高尔基体的运输没有明显的影响，但它们导致培养基中Aβ 42相对于总Aβ的比例显著增加。结果表明，突变型PS 1通过一种机制引起Aβ 42的产生增加，这种机制与APP的胞外运输的主要破坏无关。
Mutations in genes encoding presenilin-1 (PS1) and presenilin-2 (PS2) have been linked to familial forms of Alzheimer’s disease (AD). Cells expressing mutant presenilins produce elevated levels of Aβ42, the major amyloid peptide found in AD plaques. The mechanism whereby this occurs remains unknown, but the localization of presenilins to endoplasmic reticulum (ER) and Golgi compartments has suggested that they may function in intracellular trafficking pathways involved in processing β-amyloid precursor proteins (APP). To test this possibility, we coexpressed PS1(wt), PS1(M146L), or PS1(L286V) in HEK293 cells together with the LDL receptor, a classic glycoprotein marker that undergoes post-translational O-glycosylation in the Golgi compartment. Pulse-chase analysis of the receptor indicated that mutant presenilins had no effect on ER→Golgi transport. Similar results were obtained when the studies were carried out with cells expressing the Swedish variant of APP (SWAPP751) instead of the LDL receptor. Moreover, secretion of the soluble exodomain polypeptide fragments of SWAPP751that arise from α-secretase and β-secretase cleavage was not markedly affected by the PS1 mutants. Despite the lack of discernible effect of the PS1 mutants on trafficking of proteins through the Golgi apparatus, they caused a substantial increase in the proportion of Aβ42relative to total Aβ in the culture medium. The results suggest that mutant forms of PS1 cause elevated production of Aβ42by a mechanism that is independent of a major disruption of exocytic trafficking of APP.