title: The Zebrafish Equivalent of Alzheimer's Disease-Associated PRESENILIN Isoform PS2V Regulates Inflammatory and Other Responses to Hypoxic Stress.
abstract: Dominant mutations in the PRESENILIN genes PSEN1 and PSEN2 cause familial Alzheimer's disease (fAD) that usually shows onset before 65 years of age. In contrast, genetic variation at the PSEN1 and PSEN2 loci does not appear to contribute to risk for the sporadic, late onset form of the disease (sAD), leading to doubts that these genes play a role in the majority of AD cases. However, a truncated isoform of PSEN2, PS2V, is upregulated in sAD brains and is induced by hypoxia and high cholesterol intake. PS2V can increase γ-secretase activity and suppress the unfolded protein response (UPR), but detailed analysis of its function has been hindered by lack of a suitable, genetically manipulable animal model since mice and rats lack this PRESENILIN isoform. We recently showed that zebrafish possess an isoform, PS1IV, that is cognate to human PS2V. Using an antisense morpholino oligonucleotide, we can block specifically the induction of PS1IV that normally occurs under hypoxia. Here, we exploit this ability to identify gene regulatory networks that are modulated by PS1IV. When PS1IV is absent under hypoxia-like conditions, we observe changes in expression of genes controlling inflammation (particularly sAD-associated IL1B and CCR5), vascular development, the UPR, protein synthesis, calcium homeostasis, catecholamine biosynthesis, TOR signaling, and cell proliferation. Our results imply an important role for PS2V in sAD as a component of a pathological mechanism that includes hypoxia/oxidative stress and support investigation of the role of PS2V in other diseases, including schizophrenia, when these are implicated in the pathology.
authors.affiliation: Department of Genetics and Evolution, School of Biological Sciences, University of Adelaide, Adelaide, Australia.|School of Information Technology and Mathematical Sciences, Division of Information Technology, Engineering and the Environment, University of South Australia, Adelaide, Australia.|School of Biological Sciences, Faculty of Science and Engineering, Flinders University, Adelaide, Australia.
authors.forename: Esmaeil
authors.initials: E
authors.lastname: Ebrahimie
authors.affiliation: Department of Genetics and Evolution, School of Biological Sciences, University of Adelaide, Adelaide, Australia.
authors.forename: Seyyed Hani
authors.initials: SH
authors.lastname: Moussavi Nik
authors.affiliation: Department of Genetics and Evolution, School of Biological Sciences, University of Adelaide, Adelaide, Australia.
authors.forename: Morgan
authors.initials: M
authors.lastname: Newman
authors.affiliation: Centre for Cancer Biology, SA Pathology, Frome Road, Adelaide, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Van Der Hoek
authors.affiliation: Department of Genetics and Evolution, School of Biological Sciences, University of Adelaide, Adelaide, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Lardelli
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D000860:Hypoxia / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism; D046228:Microarray Analysis; D060172:Morpholinos; D016376:Oligonucleotides, Antisense; D053764:Presenilin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms; D060888:Real-Time Polymerase Chain Reaction; D019713:Receptors, CCR5 / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D060172:Morpholinos; D016376:Oligonucleotides, Antisense; D053764:Presenilin-1; D020033:Protein Isoforms; C543887:Psen1 protein, zebrafish; D019713:Receptors, CCR5; D029961:Zebrafish Proteins
keywords: Gene regulatory networks; neurodegenerative diseases; transcriptome profiling; zebrafish