title: Amyloid beta precursor protein and prion protein have a conserved interaction affecting cell adhesion and CNS development.
abstract: Genetic and biochemical mechanisms linking onset or progression of Alzheimer Disease and prion diseases have been lacking and/or controversial, and their etiologies are often considered independent. Here we document a novel, conserved and specific genetic interaction between the proteins that underlie these diseases, amyloid-β precursor protein and prion protein, APP and PRP, respectively. Knockdown of APP and/or PRNP homologs in the zebrafish (appa, appb, prp1, and prp2) produces a dose-dependent phenotype characterized by systemic morphological defects, reduced cell adhesion and CNS cell death. This genetic interaction is surprisingly exclusive in that prp1 genetically interacts with zebrafish appa, but not with appb, and the zebrafish paralog prp2 fails to interact with appa. Intriguingly, appa & appb are largely redundant in early zebrafish development yet their abilities to rescue CNS cell death are differentially contingent on prp1 abundance. Delivery of human APP or mouse Prnp mRNAs rescue the phenotypes observed in app-prp-depleted zebrafish, highlighting the conserved nature of this interaction. Immunoprecipitation revealed that human APP and PrP(C) proteins can have a physical interaction. Our study reports a unique in vivo interdependence between APP and PRP loss-of-function, detailing a biochemical interaction that considerably expands the hypothesized roles of PRP in Alzheimer Disease.
authors.affiliation: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Darcy M
authors.initials: DM
authors.lastname: Kaiser
authors.forename: Moulinath
authors.initials: M
authors.lastname: Acharya
authors.forename: Patricia L A
authors.initials: PL
authors.lastname: Leighton
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Nathalie
authors.initials: N
authors.lastname: Daude
authors.forename: Serene
authors.initials: S
authors.lastname: Wohlgemuth
authors.forename: Beipei
authors.initials: B
authors.lastname: Shi
authors.forename: W Ted
authors.initials: WT
authors.lastname: Allison
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology*; D002490:Central Nervous System / Q000166:cytology / Q000196:embryology*; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D060172:Morpholinos / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D016564:Amyloid beta-Protein Precursor; D017931:DNA Primers; D060172:Morpholinos; D011328:Prions