Abstract
BackgroundWhile prions play a central role in the pathogenesis of transmissible spongiform encephalopathies, the biology of these proteins and the pathophysiology of these diseases remain largely unknown. Since no case of bovine spongiform encephalopathy (BSE) has ever been reported in buffalo despite their phylogenetic proximity to cattle, genetic differences may be driving the different susceptibilities of these two species to BSE. We thus hypothesized that differences in expression of the most recently identified member of the prion family or Shadoo (SPRN) gene may relate to these species-specific differences.Principal FindingsWe first analyzed and compared the polymorphisms of the SPRN gene (∼4.4 kb), including the putative promoter, coding and 3′ regions, and further verified the entire ORF and putative promoter. This yielded a total of 117 fixed differences, remarkably: 1) a 12-bp insertion/deletion polymorphism in the hydrophobic domain of the cattle but not buffalo gene, introducing a four amino acid expansion/contraction in a series of 5 tandem Ala/Gly-containing repeats; 2) two fixed missense mutations (102Ser→Gly and 119Thr→Ala), and three missense mutations (92Pro>Thr/Met, 122Thr>Ile and 139Arg>Trp) in the coding region presenting different (P<0.05) genotypic and allelic frequency distributions between cattle and buffalo; and, 3) functional luciferase-reporter experiments for the predicted promoter region, consistent with a significantly higher activity in buffalo than cattle. Supporting these findings, immunoblotting revealed higher relative expression levels of Sho protein in cerebrum from buffalo than from cattle. In addition, for cattle, highest Sho expression was detected in obex, as compared to cerebrum or cerebellum.SignificanceOur findings support Sho as a non-PrP specific marker for prion infections, with obex as the best tissue source for the detection of Sho in TSE rapid tests. Moreover, these discoveries may prove advantageous for further understanding the biology of prion diseases.
Highlights
Transmissible spongiform encephalopathies (TSEs), known as prion diseases, are a class of fatal neurodegenerative maladies that affect various mammals, including cattle, sheep, mink, cervids, and humans
Gene density and GC content are much higher in the shadow of prion protein gene (SPRN) genomic environment than in other genes attached to the prion protein gene family [19]
Since buffalo are ruminants belonging to the same phylogenetic family as cattle, there is no apparent reason to envision an exempted susceptibility to bovine spongiform encephalopathy (BSE)
Summary
Transmissible spongiform encephalopathies (TSEs), known as prion diseases, are a class of fatal neurodegenerative maladies that affect various mammals, including cattle, sheep, mink, cervids, and humans. SPRN, the most recently identified member of the prion gene family, encoding for a protein (Sho) that is highly conserved among many species, from fish to mammals [4], may be functionally related to the development of prion diseases. In this regard, Sho displays several similarities with prion protein (PrP), including a highly conserved N-terminal signal sequence, a hydrophobic domain (HD) in the middle of the protein, and a Cterminal signal sequence for glycophosphotidylinositol (GPI)anchor attachment [4]. We hypothesized that differences in expression of the most recently identified member of the prion family or Shadoo (SPRN) gene may relate to these speciesspecific differences
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