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.
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 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 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 Aβ 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 Aβ that contribute to AD pathogenesis.
authors: Department of Genetics and Evolution, School of Biological Sciences.
authors: Seyyed Hani
authors: SH
authors: Moussavi Nik
authors: Department of Genetics and Evolution, School of Biological Sciences.
authors: Morgan
authors: M
authors: Newman
authors: Department of Genetics and Evolution, School of Biological Sciences.
authors: Lachlan
authors: L
authors: Wilson
authors: Department of Genetics and Evolution, School of Biological Sciences.
authors: Esmaeil
authors: E
authors: Ebrahimie
authors: Department of Genetics and Evolution, School of Biological Sciences.
authors: Simon
authors: S
authors: Wells
authors: Clinical and Experimental Pharmacology, University of Adelaide, Adelaide, SA 5005, Australia.
authors: Ian
authors: I
authors: Musgrave
authors: School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, WA 6102, Australia, Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, Joondalup, WA 6027, Australia and School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA 6009, Australia.
authors: Giuseppe
authors: G
authors: Verdile
authors: Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, Joondalup, WA 6027, Australia and School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA 6009, Australia.
authors: Ralph N
authors: RN
authors: Martins
authors: Department of Genetics and Evolution, School of Biological Sciences, michael.lardelli@adelaide.edu.au.
authors: Michael
authors: M
authors: Lardelli
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D005075:Biological Evolution; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D053766:Presenilin-2 / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; C469349:PSENEN protein, human; D010455:Peptides; D053764:Presenilin-1; D053766:Presenilin-2; C543887:Psen1 protein, zebrafish; C543888:Psen2 protein, zebrafish; D029961:Zebrafish Proteins; C510149:psenen protein, zebrafish; D053829:Amyloid Precursor Protein Secretases