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https://hdl.handle.net/2440/92720
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dc.contributor.author | Moussavi Nik, S. | - |
dc.contributor.author | Newman, M. | - |
dc.contributor.author | Wilson, L. | - |
dc.contributor.author | Ebrahimie, E. | - |
dc.contributor.author | Wells, S. | - |
dc.contributor.author | Musgrave, I. | - |
dc.contributor.author | Verdile, G. | - |
dc.contributor.author | Martins, R. | - |
dc.contributor.author | Lardelli, M. | - |
dc.date.issued | 2015 | - |
dc.identifier.citation | Human Molecular Genetics, 2015; 24(13):3662-3678 | - |
dc.identifier.issn | 1460-2083 | - |
dc.identifier.issn | 1460-2083 | - |
dc.identifier.uri | http://hdl.handle.net/2440/92720 | - |
dc.description.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. | - |
dc.description.statementofresponsibility | Seyyed Hani Moussavi Nik, Morgan Newman, Lachlan Wilson, Esmaeil Ebrahimie, Simon Wells, Ian Musgrave, Giuseppe Verdile, Ralph N. Martins, and Michael Lardelli | - |
dc.language.iso | en | - |
dc.publisher | Oxford University Press | - |
dc.rights | © The Author 2015. | - |
dc.source.uri | http://dx.doi.org/10.1093/hmg/ddv110 | - |
dc.subject | Animals | - |
dc.subject | Zebrafish | - |
dc.subject | Humans | - |
dc.subject | Alzheimer Disease | - |
dc.subject | Peptides | - |
dc.subject | Amyloid beta-Protein Precursor | - |
dc.subject | Zebrafish Proteins | - |
dc.subject | Membrane Proteins | - |
dc.subject | Female | - |
dc.subject | Male | - |
dc.subject | Amyloid Precursor Protein Secretases | - |
dc.subject | Presenilin-1 | - |
dc.subject | Presenilin-2 | - |
dc.subject | Unfolded Protein Response | - |
dc.subject | Biological Evolution | - |
dc.subject | Hypoxia | - |
dc.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 | - |
dc.title.alternative | 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 | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1093/hmg/ddv110 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/453622 | - |
dc.relation.grant | http://purl.org/au-research/grants/arc/DP1094119 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/1045507 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/1061006 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Moussavi Nik, S. [0000-0002-5727-6863] | - |
dc.identifier.orcid | Newman, M. [0000-0002-4930-4529] | - |
dc.identifier.orcid | Ebrahimie, E. [0000-0002-4431-2861] | - |
dc.identifier.orcid | Musgrave, I. [0000-0003-1016-0588] | - |
dc.identifier.orcid | Lardelli, M. [0000-0002-4289-444X] | - |
Appears in Collections: | Aurora harvest 2 Genetics publications |
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