The CNS glycoprotein Shadoo has PrPC-like protective properties and displays reduced levels in prion infections

Abstract

The cellular prion protein, PrPC, is neuroprotective in a number of settings and in particular prevents cerebellar degeneration mediated by CNS‐expressed Doppel or internally deleted PrP (‘ΔPrP’). This paradigm has facilitated mapping of activity determinants in PrPC and implicated a cryptic PrPC‐like protein, ‘π’. Shadoo (Sho) is a hypothetical GPI‐anchored protein encoded by the Sprn gene, exhibiting homology and domain organization similar to the N‐terminus of PrP. Here we demonstrate Sprn expression and Sho protein in the adult CNS. Sho expression overlaps PrPC, but is low in cerebellar granular neurons (CGNs) containing PrPC and high in PrPC‐deficient dendritic processes. In Prnp0/0 CGNs, Sho transgenes were PrPC‐like in their ability to counteract neurotoxic effects of either Doppel or ΔPrP. Additionally, prion‐infected mice exhibit a dramatic reduction in endogenous Sho protein. Sho is a candidate for π, and since it engenders a PrPC‐like neuroprotective activity, compromised neuroprotective activity resulting from reduced levels may exacerbate damage in prion infections. Sho may prove useful in deciphering several unresolved facets of prion biology.

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

“…SPRN comprises two exons, with the open reading frame (ORF) contained within exon 2, and codes for a protein of 130-150 amino acids named Shadoo (Sho, Japanese shadow) present in mammals as well as other vertebrates (Premzl et al, 2004). In a recent study, Watts and coworkers, described that Shadoo shared protective properties with PrP c (Watts et al, 2007), and stated that Sho functions counteract neurotoxic effects of either Doppel or F35 (Watts et al, 2007). In this study, Sho expression is decreased after PrP sc formation, which may also decrease the neuroprotection and enhance the development of the disease in a loss of function hypothesis of the PrP c roles (Fig.…”

“…In prnp -/-mice, although PrP c is missing Sho is able to induce a decreased neuroprotective signal, and some modified phenotype is present in these mice (2). In PrP sc infected mice levels of Sho are reduced (Watts et al, 2007). Proposed models of PrP c /receptor interaction.…”

Knockout of the prion protein (PrP)-like Sprn gene does not produce embryonic lethality in combination with PrP C -deficiency

“…More recently, the Sprn gene (20) on chromosome 7 has been shown to encode the Shadoo (Sho) glycoprotein with homology to the PrP C hydrophobic domain. Sho, like PrP, is attached to the cell surface by a GPI anchor (21). In prion infections, levels of Sho protein are markedly reduced (21)(22)(23)(24).…”

“…Sho, like PrP, is attached to the cell surface by a GPI anchor (21). In prion infections, levels of Sho protein are markedly reduced (21)(22)(23)(24). In terms of physiological action, Sho, like PrP C , can exhibit neuroprotective properties (21) and shares a number of binding partners in common with PrP C (25).…”

Current understanding of PrnP Genetics: A tool for Molecular Assisted Selection in Sheep Populations (A review)

“…The prionic protein gene belongs to a gene superfamily that comprises several orthologs (in many mammals and birds) and Doppel paralogs of gene PrnD (Prion Doppel Protein) (Moore et al, 1999) and SprnP (Shadoo Prion Protein) (Watts et al, 2007).…”