Transmissible spongiform encephalopathies (TSE) are neurodegenerative diseases caused by an infectious agent with viral properties. Host prion protein (PrP), a marker of late stage TSE pathology, is linked to a similar protein called Shadoo (Sho). Sho is reduced in mice infected with the RML scrapie agent, but has not been investigated in other TSEs. Although PrP is required for infection by TSE agents, it is not known if Sho is similarly required. Presumably Sho protects cells from toxic effects of misfolded PrP. We compared Sho and PrP changes after infection by very distinct TSE agents including sporadic CJD, Asiatic CJD, New Guinea kuru, vCJD (the UK epidemic bovine agent) and 22L sheep scrapie, all passaged in standard mice. We found that Sho reductions were agent-specific. Variable Sho reductions in standard mice could be partly explained by agent-specific differences in regional neuropathology. However, Sho did not follow PrP misfolding in any quantitative or consistent way. Tga20 mice with high murine PrP levels revealed additional agent-specific differences. Sho was unaffected by Asiatic CJD yet was markedly reduced by the kuru agent in Tga20 mice; in standard mice both agents induced the same Sho reductions. Analyses of neural GT1 cells demonstrated that Sho was not essential for TSE infections. Furthermore, because all infected GT1 cells appeared as healthy as uninfected controls, Sho was not needed to protect infected cells from their “toxic” burden of abundant abnormal PrP and intracellular amyloid.