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https://hdl.handle.net/2440/92720
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Type: | Journal article |
Title: | 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 |
Other Titles: | Alzheimer's disease-related peptide PS2V plays ancient, conserved roles in suppression of the unfolded protein response under hypoxia and stimulation of gamma-secretase activity |
Author: | Moussavi Nik, S. Newman, M. Wilson, L. Ebrahimie, E. Wells, S. Musgrave, I. Verdile, G. Martins, R. Lardelli, M. |
Citation: | Human Molecular Genetics, 2015; 24(13):3662-3678 |
Publisher: | Oxford University Press |
Issue Date: | 2015 |
ISSN: | 1460-2083 1460-2083 |
Statement of Responsibility: | Seyyed Hani Moussavi Nik, Morgan Newman, Lachlan Wilson, Esmaeil Ebrahimie, Simon Wells, Ian Musgrave, Giuseppe Verdile, Ralph N. Martins, and Michael Lardelli |
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. |
Keywords: | Animals Zebrafish Humans Alzheimer Disease Peptides Amyloid beta-Protein Precursor Zebrafish Proteins Membrane Proteins Female Male Amyloid Precursor Protein Secretases Presenilin-1 Presenilin-2 Unfolded Protein Response Biological Evolution Hypoxia |
Rights: | © The Author 2015. |
DOI: | 10.1093/hmg/ddv110 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/453622 http://purl.org/au-research/grants/arc/DP1094119 http://purl.org/au-research/grants/nhmrc/1045507 http://purl.org/au-research/grants/nhmrc/1061006 |
Published version: | http://dx.doi.org/10.1093/hmg/ddv110 |
Appears in Collections: | Aurora harvest 2 Genetics publications |
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