Prion protein function and the disturbance of early embryonic development in zebrafish

Abstract

Transmissible Spongiform Encephalopathies (TSE) or prion diseases are a threat to food safety and to human and animal health. The molecular mechanisms responsible for prion diseases share similarities with a wider group of neurodegenerative disorders including Alzheimer disease and Parkinson disease and the central pathological event is a disturbance of protein folding of a normal cellular protein that is eventually accompanied by neuronal cell death and the death of the host. Prion protein (PrP) is a constituent of most normal mammalian cells and its presence is essential in the pathogenesis of TSE. However, the function of this normal cellular protein remains unclear. The prevention of PRNP gene expression in mammalian species has been undramatic, implying a functional redundancy. Yet PrP is conserved from mammals to fish. Recent studies of PrP in zebrafish have yielded novel findings showing that PrP has essential roles in early embryonic development. The amenability of zebrafish to global technologies has generated data indicating the existence of "anchorless" splice variants of PrP in the early embryo. This paper will discuss the possibility that the experimentalist's view of PrP functions might be clearer at a greater phylogenetic distance.

Figure 1

PrP-2 gene knockdown induced differentially expressed genes involved in neurogenesis and developmental processes in 24 hpf zebrafish embryos injected with PrP-2 morpholino. Red color indicates up and green downregulation of the genes indicated. The figure was generated by Ingenuity Pathway Analysis program (IPA; www.ingenuity.com), which clusters significantly differentially expressed genes and generates a pathway and biological function analysis. The symbols for different gene products involved are presented in the top part.

Figure 2

PrP-2 mRNA splice isoforms: At least two isoforms of prnprs3 (PrP-2) mRNA are described in zebrafish; (A) A 2 exon transcript (RefSeq: NM_001013298.1; UCSC Genome Browser on Zebrafish Jul 2010) and (B) A 3 exon transcript (ENSDART00000116357, Zv9 Ensembl release 61-Feb 2011). The latter discloses an extra intron in the C-terminus of the open reading frame leading to a frame shift, which causes the C-terminal end to switch from being hydrophobic to more hydrophilic. The figure was created using CLC Main Workbench (CLC bio, Aarhus, Denmark).