Carboxyl-terminal fragments of Alzheimer β-amyloid precursor protein accumulate in restricted and unpredicted intracellular compartments in presenilin 1-deficient cells
Carboxyl-terminal fragments of Alzheimer β-amyloid precursor protein accumulate in restricted and unpredicted intracellular compartments in presenilin 1-deficient cells
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DOI：
10.1074/jbc.m006986200
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发表时间：
2000-11-24
影响因子：
4.8
通讯作者：
Fraser, PE
中科院分区：
文献类型：
--
作者：
Chen, FS;Yang, DS;Fraser, PE
缺乏功能性早老素1 （PS1）蛋白会导致γ -分泌酶对淀粉样蛋白前体蛋白（β APP）切割的丧失，导致淀粉样蛋白β肽（a β）的产生和α -或β -分泌酶切割的PAPP的cooh末端片段（α -或β - ctfs）的积累急剧减少。脑内主要的cooh末端片段（CTF）被鉴定为PAPP-CTF-(11-98)，这与培养神经元主要产生A β -的观察结果一致（11-40）。在表达功能丧失的PS1（D385A）突变体的PS1（-/-）小鼠神经元和成纤维细胞中，CTFs积聚在内质网、高尔基体和溶酶体中，但不积聚在晚期内体中。与PS1（D385A）突变成纤维细胞相比，PS1（-/-）神经元中CTFs的亚细胞分布存在细微差异。然而，在这两个突变体中，全长β APP和其他细胞器标记没有明显的再分布。内质网到高尔基体转运的阻断表明，在PS1-/-神经元（正常细胞）中，β - APP转运到高尔基体室是在α -和β -分泌酶分裂发生之前必需的。因此，尽管我们不能排除PS1在CTFs运输中的特定作用，但这些数据反对PS1在一般蛋白质运输中的主要作用。这些结果更符合PS1作为γ -分泌酶的实际催化活性或与γ -分泌酶催化间接相关的其他功能的作用。-分泌酶的激活剂，-分泌酶的底物适配器，或将-分泌酶传递到含有- app的隔室)。
Absence of functional presenilin 1 (PS1) protein leads to loss of gamma -secretase cleavage of the amyloid precursor protein (beta APP), resulting in a dramatic reduction in amyloid beta peptide (A beta) production and accumulation of alpha- or beta -secretase-cleaved COOH-terminal fragments of PAPP (alpha- or beta -CTFs). The major COOH-terminal fragment (CTF) in brain was identified as PAPP-CTF-(11-98), which is consistent with the observation that cultured neurons generate primarily A beta-(11-40). In PS1(-/-) murine neurons and fibroblasts expressing the loss-of-function PS1(D385A) mutant, CTFs accumulated in the endoplasmic reticulum, Golgi, and lysosomes, but not late endosomes. There were some subtle differences in the subcellular distribution of CTFs in PS1(-/-) neurons as compared with PS1(D385A) mutant fibroblasts. However, there was no obvious redistribution of full-length beta APP or of markers of other organelles in either mutant. Blockade of endoplasmic reticulum-to-Golgi trafficking indicated that in PS1-/- neurons las in normal cells) trafficking of beta APP to the Golgi compartment is necessary before alpha- and beta -secretase cleavages occur. Thus, although we cannot exclude a specific role for PS1 in trafficking of CTFs, these data argue against a major role in general protein trafficking. These results are more compatible with a role for PS1 either as the actual gamma -secretase catalytic activity or in other functions indirectly related to gamma -secretase catalysis (e,g. an activator of gamma -secretase, a substrate adaptor for gamma -secretase, or delivery of gamma -secretase to beta APP-containing compartments).