[Frontiers in Bioscience 16, 1505-1516, January 1, 2011]

Biological properties of the PrP-like Shadoo protein

Nathalie Daude, David Westaway

Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada


1. Abstract
2. Introduction
3. SPRN gene expression
3.1. Expression of SPRN mRNA
3.1.1. Mice
3.1.2. Sheep
3.1.3. Cattle
3.1.4. Humans
3.2. Synthesis, maturation and structure of the Shadoo protein
3.2.1. Studies in silico
3.2.2. Shadoo in vitro
4. Shadoo and cellular physiology
4.1. Pathways and binding partners
4.2. Neuroanatomical expression and function
5. Shadoo and the pathogenesis of prion disease
5.1. Down-regulation of Shadoo protein in prion-infected mice
5.2. Shadoo and scrapie disease of sheep
5.3. Germline SPRN mutations and human prion disease
6. Perspective
7. Acknowledgments
8. References


The SPRN gene encodes the Shadoo glycoprotein (Sho), a central nervous system-expressed member of the prion protein superfamily. Sho has similarity to two features within PrPC's natively unstructured N-terminus, a hydrophobic domain and tandem repeats with positively charged residues. Indeed, scrutiny of Sho's biochemical properties in uninfected cells has revealed overlaps with the properties of PrPC, these including shared protein binding partners. SPRN is conserved in mammals, as is the prion gene PRNP, but in sheep SPRN and PRNP are both marked by polymorphic variation, suggestive of a shared selection pressure within these scrapie disease-prone livestock animals. In rodent models of prion disease there are reduced levels of Sho in infected tissues, defining a form of cross-regulation between full-length Sho holoprotein and PrPSc. In human prion disease an SPRN signal peptide polymorphism is associated with risk for sporadic Creutzfeldt-Jakob Disease (CJD), while two patients with early-onset variant CJD carried putatively inactive SPRN alleles. Further investigation of Sho as a novel tracer or modifier for the accumulation of pathologic forms of PrP may prove advantageous.