Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/92720
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dc.contributor.authorMoussavi Nik, S.-
dc.contributor.authorNewman, M.-
dc.contributor.authorWilson, L.-
dc.contributor.authorEbrahimie, E.-
dc.contributor.authorWells, S.-
dc.contributor.authorMusgrave, I.-
dc.contributor.authorVerdile, G.-
dc.contributor.authorMartins, R.-
dc.contributor.authorLardelli, M.-
dc.date.issued2015-
dc.identifier.citationHuman Molecular Genetics, 2015; 24(13):3662-3678-
dc.identifier.issn1460-2083-
dc.identifier.issn1460-2083-
dc.identifier.urihttp://hdl.handle.net/2440/92720-
dc.description.abstractThe 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.-
dc.description.statementofresponsibilitySeyyed Hani Moussavi Nik, Morgan Newman, Lachlan Wilson, Esmaeil Ebrahimie, Simon Wells, Ian Musgrave, Giuseppe Verdile, Ralph N. Martins, and Michael Lardelli-
dc.language.isoen-
dc.publisherOxford University Press-
dc.rights© The Author 2015.-
dc.source.urihttp://dx.doi.org/10.1093/hmg/ddv110-
dc.subjectAnimals-
dc.subjectZebrafish-
dc.subjectHumans-
dc.subjectAlzheimer Disease-
dc.subjectPeptides-
dc.subjectAmyloid beta-Protein Precursor-
dc.subjectZebrafish Proteins-
dc.subjectMembrane Proteins-
dc.subjectFemale-
dc.subjectMale-
dc.subjectAmyloid Precursor Protein Secretases-
dc.subjectPresenilin-1-
dc.subjectPresenilin-2-
dc.subjectUnfolded Protein Response-
dc.subjectBiological Evolution-
dc.subjectHypoxia-
dc.titleAlzheimer's disease-related peptide PS2V plays ancient, conserved roles in suppression of the unfolded protein response under hypoxia and stimulation of γ-secretase activity-
dc.title.alternativeAlzheimer's disease-related peptide PS2V plays ancient, conserved roles in suppression of the unfolded protein response under hypoxia and stimulation of gamma-secretase activity-
dc.typeJournal article-
dc.identifier.doi10.1093/hmg/ddv110-
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/453622-
dc.relation.granthttp://purl.org/au-research/grants/arc/DP1094119-
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1045507-
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1061006-
pubs.publication-statusPublished-
dc.identifier.orcidMoussavi Nik, S. [0000-0002-5727-6863]-
dc.identifier.orcidNewman, M. [0000-0002-4930-4529]-
dc.identifier.orcidEbrahimie, E. [0000-0002-4431-2861]-
dc.identifier.orcidMusgrave, I. [0000-0003-1016-0588]-
dc.identifier.orcidLardelli, M. [0000-0002-4289-444X]-
Appears in Collections:Aurora harvest 2
Genetics publications

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