Shadoo (Sprn) and prion disease incubation time in mice

Abstract

Prion diseases are transmissible neurodegenerative disorders of mammalian species and include scrapie, bovine spongiform encephalopathy (BSE), and variant Creutzfeldt-Jakob disease (vCJD). The prion protein (PrP) plays a key role in the disease, with coding polymorphism in both human and mouse influencing disease susceptibility and incubation time, respectively. Other genes are also thought to be important and a plausible candidate is Sprn , which encodes the PrP-like protein Shadoo (Sho). Sho is expressed in the adult central nervous system and exhibits neuroprotective activity reminiscent of PrP in an in vitro assay. To investigate the role of Sprn in prion disease incubation time we sequenced the open reading frame (ORF) in a diverse panel of mice and saw little variation except in strains derived from wild-trapped mice. Sequencing the untranslated regions revealed polymorphisms that allowed us to carry out an association study of incubation period in the Northport heterogeneous stock of mice inoculated with Chandler/RML prions. We also examined the expression level of Sprn mRNA in the brains of normal and prion-infected mice and saw no correlation with either genotype or incubation time. We therefore conclude that Sprn does not play a major role in prion disease incubation time in these strains of mice.

Down-Regulation of Shadoo in Prion Infections Traces a Pre-Clinical Event Inversely Related to PrPSc Accumulation

“…These small alterations in Sprn mRNA levels are consistent with experimental noise and cannot explain the 4- to 8-fold decrements in the Sho protein, as documented herein and previously [17], [38]. These microarray data are in agreement with much smaller studies from other laboratories [39] where Sprn mRNA levels were sometimes slightly elevated, compared to the Sho protein down-regulation regularly seen in diverse models of prion disease. Thus, reduction in Sho protein in animals with different types of prion infections was not paralleled by a consistent reduction in transcript level.…”

Frequent Missense and Insertion/Deletion Polymorphisms in the Ovine Shadoo Gene Parallel Species-Specific Variation in PrP

“…In this study, we assessed polymorphisms of the Sho gene of humans, mice and sheep. We find that mice have little coding sequence variation in this gene, in accord with a recent study based on a different sample set [18] . In the case of human SPRN we confirmed a signal peptide M7T variation was found in our sample of Caucasian DNAs (and as reported previously by others [19] ), but we were unable to define a high frequency polymorphism within the boundaries of the mature human Sho protein (residues 24 to 126).…”

Agent-specific Shadoo Responses in Transmissible Encephalopathies

“…Sho was not reduced at the mRNA level (Lloyd et al 2009). This indicates functional nuclear transcription with either nonfunctional Sho synthesis at the ER level, or the post-synthetic destruction of Sho in cellular compartments such as lysosomes.…”

“…On the other hand, Sho exhibited no clear neuroprotective role in infected mice. Although infection with the RML scrapie agent induced widespread spongiform lesions and a corresponding reduction of Sho (Watts et al 2007), Sho did not reduce the incubation time to neurological disease (Gossner et al 2009; Lloyd et al 2009). …”