Moussavi Nik Seyyed Hani, Newman Morgan, Wilson Lachlan, Ebrahimie Esmaeil, Wells Simon, Musgrave Ian, Verdile Giuseppe, Martins Ralph N, Lardelli Michael
Department of Genetics and Evolution, School of Biological Sciences.
Clinical and Experimental Pharmacology, University of Adelaide, Adelaide, SA 5005, Australia.
Hum Mol Genet. 2015 Jul 1;24(13):3662-78. doi: 10.1093/hmg/ddv110. Epub 2015 Mar 26.
The PRESENILIN1 and PRESENILIN2 genes encode structurally related proteases essential for γ-secretase activity. Of nearly 200 PRESENILIN mutations causing early onset, familial Alzheimer's disease (FAD) only the K115Efx10 mutation of PSEN2 causes truncation of the open reading frame. If translated, the truncated product would resemble a naturally occurring isoform of PSEN2 named PS2V that is induced by hypoxia and found at elevated levels in late onset Alzheimer's disease (AD) brains. The function of PS2V is largely unexplored. We show that zebrafish possess a PS2V-like isoform, PS1IV, produced from the fish's PSEN1 rather than PSEN2 orthologous gene. The molecular mechanism controlling formation of PS2V/PS1IV was probably present in the ancient common ancestor of the PSEN1 and PSEN2 genes. Human PS2V and zebrafish PS1IV have highly divergent structures but conserved abilities to stimulate γ-secretase activity and to suppress the unfolded protein response (UPR) under hypoxia. The putative protein truncation caused by K115Efx10 resembles PS2V in its ability to increase γ-secretase activity and suppress the UPR. This supports increased Aβ levels as a common link between K115Efx10 early onset AD and sporadic, late onset AD. The ability of mutant variants of PS2V to stimulate γ-secretase activity partially correlates with their ability to suppress the UPR. The cytosolic, transmembrane and luminal domains of PS2V are all critical to its γ-secretase and UPR-suppression activities. Our data support a model in which chronic hypoxia in aged brains promotes excessive Notch signalling and accumulation of Aβ that contribute to AD pathogenesis.
早老素1（PRESENILIN1）基因和早老素2（PRESENILIN2）基因编码对γ-分泌酶活性至关重要的结构相关蛋白酶。在近200种导致早发性家族性阿尔茨海默病（FAD）的早老素突变中，只有PSEN2基因的K115Efx10突变会导致开放阅读框截断。如果进行翻译，截短产物将类似于PSEN2的一种天然存在的异构体PS2V，它由缺氧诱导，在晚发性阿尔茨海默病（AD）大脑中水平升高。PS2V的功能在很大程度上尚未被探索。我们发现斑马鱼拥有一种类似PS2V的异构体PS1IV，它由鱼类的PSEN1而非PSEN2直系同源基因产生。控制PS2V/PS1IV形成的分子机制可能存在于PSEN1和PSEN2基因的古老共同祖先中。人类PS2V和斑马鱼PS1IV具有高度不同的结构，但在缺氧条件下刺激γ-分泌酶活性和抑制未折叠蛋白反应（UPR）的能力保守。由K115Efx10导致的假定蛋白截短在增加γ-分泌酶活性和抑制UPR的能力方面类似于PS2V。这支持了Aβ水平升高是K115Efx10早发性AD与散发性晚发性AD之间的共同联系。PS2V突变变体刺激γ-分泌酶活性的能力与其抑制UPR的能力部分相关。PS2V的胞质、跨膜和腔内结构域对其γ-分泌酶和UPR抑制活性均至关重要。我们的数据支持一种模型，即老年大脑中的慢性缺氧促进Notch信号过度激活和Aβ积累，这有助于AD发病机制。
