Neuroprotective properties of the PrP-like Shadoo glycoprotein assessed in the middle cerebral artery occlusion model of ischemia

Biochemical similarities have been noted between the natively unstructured region of the cellular prion protein, PrP^C, and a GPI-linked glycoprotein called Shadoo (Sho); these proteins are encoded by the <i>Prnp</i> and <i>Sprn</i> genes, respectively. Both proteins are expressed in the adult central nervous system and they share overlapping partners, including each other, in interactome studies. As prior studies have ascribed neuroprotective properties to the N-terminal region of PrP^C, specifically the octarepeat region, we investigated Sho's neuroprotective properties. To this end we assessed Sho-null (<i>Sprn</i>^0/0) and hemizygous (<i>Sprn</i>^{<i><i>0</i>/+</i>}) mice in the middle cerebral artery occlusion (MCAO) model versus wild type mice and also vs. transgene-rescued <i>Sprn</i>^0/0-Tg<i>Sprn</i> mice. <i>Sprn</i>^0/0 mice had a tendency to greater fragility in reaching endpoint and deficits in parameters including infarct volume and neurogenesis, with a reciprocal trend noted in transgene-rescued mice; however these effects did not reach significance. Loss of both PrP^C and Sho immunostaining occurred in parallel to neuronal loss on the ipsilateral side of MCAO-lesioned animals; while focal elevations in immunostaining in the penumbra region were sometimes evident for PrP^C, they were not noted for Sho. Our studies argue against discernible neuroprotective action of Sho in the genetic backgrounds used for this MCAO paradigm. Whether or not the positively charged N-terminal regions in Sho and PrP^C fulfil different roles <i>in vivo</i> remains to be determined.