Alzheimer's disease-related peptide PS2V plays ancient, conserved roles in suppression of the unfolded protein response under hypoxia and stimulation of ?-secretase activity
MetadataShow full item record
The PRESENILIN1 and PRESENILIN2 genes encode structurally related proteases essential for ?-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 ?-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 ?-secretase activity and suppress the UPR. This supports increased Aß levels as a common link between K115Efx10 early onset AD and sporadic, late onset AD. The ability of mutant variants of PS2V to stimulate ?-secretase activity partially correlates with their ability to suppress the UPR. The cytosolic, transmembrane and luminal domains of PS2V are all critical to its ?-secretase and UPR-suppression activities. Our data support a model in which chronic hypoxia in aged brains promotes excessive Notch signalling and accumulation of Aß that contribute to AD pathogenesis.
Showing items related by title, author, creator and subject.
Evidence for and against a pathogenic role for reduced γ-secretase activity in familial Alzheimer’s diseaseVerdile, Giuseppe; Jayne, T.; Newman, M.; Sutherland, G.; Munch, G.; Musgrave, I.; Moussavi Nik, H.; Lardelli, M. (2016)The majority of mutations causing familial Alzheimer’s disease (fAD) have been found in the gene PRESENILIN1 (PSEN1 ) with additional mutations in the related gene PRESENILIN2 (PSEN2 ). The best characterized function of ...
The Guinea Pig as a Model for Sporadic Alzheimer’s Disease (AD): The Impact of Cholesterol Intake on Expression of AD-Related GenesSharman, Matthew; Moussavi Nik, Seyyed; Chen, Mengqi; Ong, Daniel; Wijaya, Linda; Laws, Simon; Taddei, Kevin; Newman, Morgan; Lardelli, Michael; Martins, Ralph; Verdile, Giuseppe (2013)We investigated the guinea pig, Cavia porcellus, as a model for Alzheimer’s disease (AD), both in terms of the conservation of genes involved in AD and the regulatory responses of these to a known AD risk factor - high ...
Dysregulation of neuronal iron homeostasis as an alternative unifying effect of mutations causing familial Alzheimer's diseaseLumsden, A.; Rogers, J.; Majd, S.; Newman, M.; Sutherland, G.; Verdile, Giuseppe; Lardelli, M. (2018)The overwhelming majority of dominant mutations causing early onset familial Alzheimer's disease (EOfAD) occur in only three genes, PSEN1, PSEN2, and APP. An effect-in-common of these mutations is alteration of production ...