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 PrPC 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.

Cellular prion protein modulates β-amyloid deposition in aged APP/PS1 transgenic mice

“…These parameters peaked in 9-month-old mice, suggesting a time-dependent interaction between PrP c and amyloid burden. It is possible that the seeding effect attributed to Ab (Kane et al, 2000;Langer et al, 2011) may be enhanced by PrP c , which colocalizes with Ab (Kaiser et al, 2012). In fact interaction between PrP c and Ab42 has been reported (Lauren et al, 2009).…”

Prion gene paralogs are dispensable for early zebrafish development and have nonadditive roles in seizure susceptibility

“…We recently engineered mutations of prp2 and were surprised to observe that the fish developed normally, with phenotypes that included deeply conserved roles in NMDA receptor dysregulation, learning/memory, and seizure susceptibility (16,27). This contrasted several works (including our own) using prion knockdown to produce dramatic early defects and suggested that PrP C is required for embryonic development (16,22,28). To reconcile this discrepancy, we hypothesized that the two PrP C paralogs in zebrafish, prp1 and prp2, might have partially redundant roles such that prp1 was masking phenotypes in our prp2 mutants.…”

“…The mammalian and fish homologs do not share high percent identity, as the latter are longer, but both are predicted to have the repeat domains, hydrophobic domains, glycine zippers, and posttranslational modifications (GPI-anchor, disulfide bridge, and N-linked glycosylations) that are present in the canonical mammalian prion protein (15, 16, 19 -21). The functional conservation among these genes is strongly supported by experiments where mammalian prion proteins rescue phenotypes observed following disruption of fish prion genes (18,22,23). The reciprocal approach expressing fish PrP C in mammalian cells demonstrates that fish PrP C has post-translational modifications (glycosylation) similar to its mammalian homologs (20,24).…”

Brain immune interactions and air pollution: macrophage inhibitory factor (MIF), prion cellular protein (PrPC), Interleukin-6 (IL-6), interleukin 1 receptor antagonist (IL-1Ra), and interleukin-2 (IL-2) in cerebrospinal fluid and MIF in serum differentiate urban children exposed to severe vs. low air pollution

“…The PRNP gene located in chromosome 20 likely plays key roles in neuronal development, synaptic plasticity, myelin sheath maintenance, cell adhesion, CNS development, and neuroprotection via inhibition of the mitochondrial apoptotic pathway (Mitsios et al, 2007; Altmeppen et al, 2012; Bradford and Mabbott, 2012; Kaiser et al, 2012; Ding et al, 2013). …”