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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Dissociated phenotypes in presenilin transgenic mice define functionally distinct gamma-secretases
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Dissociated phenotypes in presenilin transgenic mice define functionally distinct gamma-secretases

机译：早老素转基因小鼠中的解离表型定义了功能上不同的γ-分泌酶

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摘要

gamma-secretase depends on presence of presenilins (PS), Nct, Aph-1, and PEN-2 within a core complex. This endoproteolytic activity cleaves within transmembrane domains of amyloid-beta precursor protein (APP) and Notch, and familial Alzheimer's disease (FAD) mutations in PS1 or PS2 genes shift APP cleavage from production of amyloid-beta (A beta) 40 peptide to greater production of A beta 42. Although studies in PS1/PS2-deficient embryonic cells define overlapping activities for these proteins, in vivo complementation of PS1-deficient animals described here reveals an unexpected spectrum of activities dictated by PS1 and PS2 alleles. Unlike PS1 transgenes, wild-type PS2 transgenes expressed in the mouse CNS support little A beta 40 or A beta 42 production, and FAD PS2 alleles support robust production of only A beta 42. Although wild-type PS2 transgenes failed to rescue Notch-associated skeletal defects in PS1 hypomorphs, a "gained" competence in this regard was apparent for FAD alleles of PS2. The range of discrete and divergent processing activities in mice reconstituted with different PS genes and alleles argues against gamma-secretase being a single enzyme with intrinsically relaxed substrate and cleavage site specificities. Instead, our studies define functionally distinct gamma-secretase variants. We speculate that extrinsic components, in combination with core complexes, may tailor functional variants of this enzyme to their preferred substrates.
机译：γ-分泌酶取决于核心复合物中是否存在早老蛋白（PS），Nct，Aph-1和PEN-2。这种内蛋白水解活性在淀粉样蛋白β前体蛋白（APP）和Notch的跨膜结构域内裂解，并且PS1或PS2基因的家族性阿尔茨海默氏病（FAD）突变将APP裂解从淀粉样蛋白β（A beta）40肽的产生转移到更大的产量β42的表达。尽管在PS1 / PS2缺陷型胚胎细胞中的研究定义了这些蛋白质的重叠活性，但此处描述的PS1缺陷型动物的体内互补显示出PS1和PS2等位基因决定的意外活性谱。与PS1转基因不同，在小鼠CNS中表达的野生型PS2转基因几乎不支持A beta 40或A beta 42的生产，而FAD PS2等位基因仅支持稳健的A beta 42的生产。尽管野生型PS2转基因无法挽救与Notch相关的基因对于PS2的FAD等位基因，PS1亚型的骨骼缺陷明显具有“增强”的能力。用不同的PS基因和等位基因重组的小鼠中离散和发散的加工活性范围反对γ-分泌酶是具有固有的底物和切割位点特异性的单一酶。相反，我们的研究定义了功能上不同的γ-分泌酶变体。我们推测，外在成分与核心复合物结合，可以使该酶的功能变体适应其优选的底物。

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