Curtin University Homepage
  • Library
  • Help
    • Admin

    espace - Curtin’s institutional repository

    JavaScript is disabled for your browser. Some features of this site may not work without it.
    View Item 
    • espace Home
    • espace
    • Curtin Research Publications
    • View Item
    • espace Home
    • espace
    • Curtin Research Publications
    • View Item

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

    Access Status
    Open access via publisher
    Authors
    Nik, S.
    Newman, M.
    Wilson, L.
    Ebrahimie, E.
    Wells, S.
    Musgrave, I.
    Verdile, Giuseppe
    Martins, R.
    Lardelli, M.
    Date
    2015
    Type
    Journal Article
    
    Metadata
    Show full item record
    Citation
    Nik, S. and Newman, M. and Wilson, L. and Ebrahimie, E. and Wells, S. and Musgrave, I. and Verdile, G. et al. 2015. Alzheimer's disease-related peptide PS2V plays ancient, conserved roles in suppression of the unfolded protein response under hypoxia and stimulation of ?-secretase activity. Human Molecular Genetics. 24 (13): pp. 3662-3678.
    Source Title
    Human Molecular Genetics
    DOI
    10.1093/hmg/ddv110
    ISSN
    0964-6906
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/37415
    Collection
    • Curtin Research Publications
    Abstract

    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.

    Related items

    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 disease
      Verdile, 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 Genes
      Sharman, 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 disease
      Lumsden, 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 ...
    Advanced search

    Browse

    Communities & CollectionsIssue DateAuthorTitleSubjectDocument TypeThis CollectionIssue DateAuthorTitleSubjectDocument Type

    My Account

    Admin

    Statistics

    Most Popular ItemsStatistics by CountryMost Popular Authors

    Follow Curtin

    • 
    • 
    • 
    • 
    • 

    CRICOS Provider Code: 00301JABN: 99 143 842 569TEQSA: PRV12158

    Copyright | Disclaimer | Privacy statement | Accessibility

    Curtin would like to pay respect to the Aboriginal and Torres Strait Islander members of our community by acknowledging the traditional owners of the land on which the Perth campus is located, the Whadjuk people of the Nyungar Nation; and on our Kalgoorlie campus, the Wongutha people of the North-Eastern Goldfields.