Alzheimer's disease-related peptide PS2V plays ancient, conserved roles in suppression of the unfolded protein response under hypoxia and stimulation of γ-secretase activity

Abstract

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 zebra fi sh possess a PS2V-like isoform, PS1IV, produced from the fi sh ’ s PSEN1 rather than PSEN2 orthologous gene. The molecular mechanism controlling formation of PS2V/PS1IV was probably present in the ancient common ancestorof the PSEN1 and PSEN2 genes. Human PS2Vand zebra fi sh 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 A β 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 A β that contribute to AD pathogenesis.